Ether compounds

ABSTRACT

The present invention relates to novel ether compounds, compositions comprising ether compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising an ether compound. The compounds, compositions, and methods of the invention are also useful for treating and preventing Alzheimer&#39;s Disease, Syndrome X, peroxisome proliferator activated receptor-related disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.

This application is a continuation of U.S. application Ser. No.09/540,738, filed Mar. 31, 2000, now U.S. Pat. No. 6,459,003, whichclaims the benefit of U.S. Provisional Application No. 60/127,321, filedApr. 1, 1999, each application being incorporated by reference herein inits entirety.

1. FIELD OF THE INVENTION

The present invention relates to ether compounds and pharmaceuticallyacceptable salts thereof; methods for synthesizing the ether compounds;compositions comprising an ether compound or a pharmaceuticallyacceptable salt thereof; and methods for treating or preventing adisease or disorder selected from the group consisting of acardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder ofglucose metabolism, Alzheimer's Disease, Syndrome X, a peroxisomeproliferator activated receptor-associated disorder, septicemia, athrombotic disorder, obesity, pancreatitis, hypertension, renal disease,cancer, inflammation, and impotence, comprising administering atherapeutically effective amount of a composition comprising an ethercompound or a pharmaceutically acceptable salt thereof. The ethercompounds and compositions of the invention may also be used to reducethe fat content of meat in livestock and reduce the cholesterol contentof eggs.

2. BACKGROUND OF THE INVENTION

Obesity, hyperlipidemia, and diabetes have been shown to play a casualrole in atherosclerotic cardiovascular diseases, which currently accountfor a considerable proportion of morbidity in Western society. Further,one human disease, termed “Syndrome X” or “Metabolic Syndrome”, ismanifested by defective glucose metabolism (insulin resistance),elevated blood pressure (hypertension), and a blood lipid imbalance(dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.

The evidence linking elevated serum cholesterol to coronary heartdisease is overwhelming. Circulating cholesterol is carried by plasmalipoproteins, which are particles of complex lipid and proteincomposition that transport lipids in the blood. Low density lipoprotein(LDL) and high density lipoprotein (HDL) are the majorcholesterol-carrier proteins. LDL are believed to be responsible for thedelivery of cholesterol from the liver, where it is synthesized orobtained from dietary sources, to extrahepatic tissues in the body. Theterm “reverse cholesterol transport” describes the transport ofcholesterol from extrahepatic tissues to the liver, where it iscatabolized and eliminated. It is believed that plasma HDL particlesplay a major role in the reverse transport process, acting as scavengersof tissue cholesterol. HDL is also responsible for the removalnon-cholesterol lipid, oxidized cholesterol and other oxidized productsfrom the bloodstream.

Atherosclerosis, for example, is a slowly progressive diseasecharacterized by the accumulation of cholesterol within the arterialwall. Compelling evidence supports the belief that lipids deposited inatherosclerotic lesions are derived primarily from plasma apolipoproteinB (apo B)-containing lipoproteins, which include chylomicrons, CLDL, IDLand LDL. The apo B-containing lipoprotein, and in particular LDL, haspopularly become known as the “bad” cholesterol. In contrast, HDL serumlevels correlate inversely with coronary heart disease. Indeed, highserum levels of HDL is regarded as a negative risk factor. It ishypothesized that high levels of plasma HDL is not only protectiveagainst coronary artery disease, but may actually induce regression ofatherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation86:(Suppl. III)86-94; Dansky and Fisher, 1999, Circulation 100:1762-3.). Thus, HDL has popularly become known as the “good”cholesterol.

2.1. Cholesterol Transport

The fat-transport system can be divided into two pathways: an exogenousone for cholesterol and triglycerides absorbed from the intestine and anendogenous one for cholesterol and triglycerides entering thebloodstream from the liver and other non-hepatic tissue.

In the exogenous pathway, dietary fats are packaged into lipoproteinparticles called chylomicrons, which enter the bloodstream and delivertheir triglycerides to adipose tissue for storage and to muscle foroxidation to supply energy. The remnant of the chylomicron, whichcontains cholesteryl esters, is removed from the circulation by aspecific receptor found only on liver cells. This cholesterol thenbecomes available again for cellular metabolism or for recycling toextrahepatic tissues as plasma lipoproteins.

In the endogenous pathway, the liver secretes a large, very-low-densitylipoprotein particle (VLDL) into the bloodstream. The core of VLDLconsists mostly of triglycerides synthesized in the liver, with asmaller amount of cholesteryl esters either synthesized in the liver orrecycled from chylomicrons. Two predominant proteins are displayed onthe surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoproteinE (apo E), although other apolipoproteins are present, such asapolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII). When aVLDL reaches the capillaries of adipose tissue or of muscle, itstriglyceride is extracted. This results in the formation of a new kindof particle called intermediate-density lipoprotein (IDL) or VLDLremnant, decreased in size and enriched in cholesteryl esters relativeto a VLDL, but retaining its two apoproteins.

In human beings, about half of the IDL particles are removed from thecirculation quickly, generally within two to six hours of theirformation. This is because IDL particles bind tightly to liver cells,which extract IDL cholesterol to make new VLDL and bile acids. The IDLnot taken up by the liver is catabolized by the hepatic lipase, anenzyme bound to the proteoglycan on liver cells. Apo E dissociates fromIDL as it is transformed to LDL. Apo B-100 is the sole protein of LDL.

Primarily, the liver takes up and degrades circulating cholesterol tobile acids, which are the end products of cholesterol metabolism. Theuptake of cholesterol-containing particles is mediated by LDL receptors,which are present in high concentrations on hepatocytes. The LDLreceptor binds both apo E and apo B-100 and is responsible for bindingand removing both LDL and LDL from the circulation. IN addition, remnantreceptors are responsible for clearing chylomicrons and VLDL remnantsi.e., IDL). However, the affinity of apo E for the LDL receptor isgreater than that of apo B-100. As a result, the LDL particles have amuch longer circulating life span than IDL particles; LDL circulates foran average of two and a half days before binding to the LDL receptors inthe liver and other tissues. High serum levels of LDL, the “bad”cholesterol, are positively associated with coronary heart disease. Forexample, in atherosclerosis, cholesterol derived from circulating LDLaccumulates in the walls of arteries. This accumulation forms bulkyplaques that inhibit the flow of blood until a clot eventually forms,obstructing an artery and causing a heart attack or stroke.

Ultimately, the amount of intracellular cholesterol liberated from theLDL controls cellular cholesterol metabolism. The accumulation ofcellular cholesterol derived from VLDL and LDL controls three processes.First, it reduces the cell's ability to make its own cholesterol byturning off the synthesis of HMGCoA reductase, a key enzyme in thecholesterol biosynthetic pathway. Second, the incoming LDL-derivedcholesterol promotes storage of cholesterol by the action of ACAT, thecellular enzyme that converts cholesterol into cholesteryl esters thatare deposited in storage droplets. Third, the accumulation ofcholesterol within the cell drives a feedback mechanism that inhibitscellular synthesis of new LDL receptors. Cells, therefore, adjust theircomplement of LDL receptors so that enough cholesterol is brought in tomeet their metabolic needs, without overloading (for a review, see Brown& Goldstein, In, The Pharmacological Basis Of Therapeutics, 8th Ed.,Goodman & Gilman, Pergaman Press, NY, 1990, Ch. 36, pp. 874-896).

High levels of apo B-containing lipoproteins can be trapped in thesubendothelial space of an artery and undergo oxidation. The oxidizedlipoprotein is recognized by scavenger receptors on macrophages. Bindingof oxidized lipoprotein to the scavenger receptors can enrich themacrophages with cholesterol and cholesteryl esters independently of theLDL receptor. Macrophages can also produce cholesteryl esters by theaction of ACAT. LDL can also be complexed to a high molecular weightglycoprotein called apolipoprotein(a), also known as apo(a), through adisulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) orLp(a). Elevated levels of Lp(a) are detrimental, having been associatedwith atherosclerosis, coronary heart disease, myocardial infarcation,stroke, cerebral infarction, and restenosis following angioplasty.

2.2. Reverse Cholesterol Transport

Peripheral (non-hepatic) cells predominantly obtain their cholesterolfrom a combination of local synthesis and uptake of preformed sterolfrom VLDL and LDL. Cells expressing scavenger receptors, such asmacrophages and smooth muscle cells, can also obtain cholesterol fromoxidized apo B-containing lipoproteins. In contrast, reverse cholesteroltransport (RCT) is the pathway by which peripheral cell cholesterol canbe returned to the liver for recycling to extrahepatic tissues, hepaticstorage, or excretion into the intestine in bile. The RCT pathwayrepresents the only means of eliminating cholesterol from mostextrahepatic tissues and is crucial to maintenance of the structure andfunction of most cells in the body.

The enzyme in blood involved in the RCT pathway, lecithin:cholesterolacyltransferase (LCAT), converts cell-derived cholesterol to cholesterylesters, which are sequestered in HDL destined for removal. LCAT isproduced mainly in the liver and circulates in plasma associated withthe HDL fraction. Cholesterol ester transfer protein (CETP) and anotherlipid transfer protein, phospholipid transfer protein (PLTP), contributeto further remodeling the circulating HDL population (see for exampleBruce et al., 1998, Annu. Rev. Nutr. 18:297-330). PLTP supplies lecithinto HDL, and CETP can move cholesteryl ester made by LCAT to otherlipoproteins, particularly apoB-containing lipoproteins, such as VLDL.HDL triglyceride can be catabolized by the extracellular hepatictriglyceride lipase, and lipoprotein cholesterol is removed by the livervia several mechanisms.

Each HDL particle contains at least one molecule, and usually two tofour molecules, of apolipoprotein (apo A-I). Apo A-I is synthesized bythe liver and small intestine as preproapolipoprotein which is secretedas a proprotein that is rapidly cleaved to generate a mature polypeptidehaving 243 amino acid residues. Apo A-I consists mainly of a 22 aminoacid repeating segment, spaced with helix-breaking proline residues. ApoA-I forms three types of stable structures with lipids: small,lipid-poor complexes referred to as pre-beta-1HDL; flattened discoidalparticles, referred to as pre-beta-2 HDL, which contain only polarlipids (e.g., phospholipid and cholesterol); and spherical particlescontaining both polar and nonpolar lipids, referred to as spherical ormature HDL (HDL₃ and HDL₂). Most HDL in the circulating populationcontains both apo A-I and apo A-II, a second major HDL protein. This apoA-I- and apo A-II-containing fraction is referred to herein as theAI/AII-HDL fraction of HDL. But the fraction of HDL containing only apoA-I, referred to herein as the AI-HDL fraction, appears to be moreeffective in RCT. Certain epidemiologic studies support the hypothesisthat the AM-HDL fraction is antiartherogenic (Parra et al., 1992,Arterioscler. Thromb. 12:701-707; Decossin et al., 1997, Eur. J. Clin.Invest. 27:299-307).

Although the mechanism for cholesterol transfer from the cell surface isunknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, isthe preferred acceptor for cholesterol transferred from peripheraltissue involved in RCT. Cholesterol newly transferred to pre-beta-1 HDLfrom the cell surface rapidly appears in the discoidal pre-beta-2 HDL.PLTP may increase the rate of disc formation (Lagrost et al., 1996, J.Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCTis lacking. LCAT reacts preferentially with discoidal and spherical HDL,transferring the 2-acyl group of lecithin or phosphatidylethanolamine tothe free hydroxyl residue of fatty alcohols, particularly cholesterol,to generate cholesteryl esters (retained in the HDL) and lysolecithin.The LCAT reaction requires an apoliprotein such apo A-I or apo A-IV asan activator. ApoA-I is one of the natural cofactors for LCAT. Theconversion of cholesterol to its HDL-sequestered ester prevents re-entryof cholesterol into the cell, resulting in the ultimate removal ofcellular cholesterol. Cholesteryl esters in the mature HDL particles ofthe AI-HDL fraction are removed by the liver and processed into bilemore effectively than those derived from the AI/AII-HDL fraction. Thismay be due, in part, to the more effective binding of AI-HDL to thehepatocyte membrane. Several HDL receptor receptors have beenidentified, the most well characterized of which is the scavengerreceptor class B, type I (SR-BI) (Acton et al., 1996, Science271:518-520). The SR-BI is expressed most abundantly in steroidogenictissues (e.g., the adrenals), and in the liver (Landshulz et al., 1996,J. Clin. Invest 98:984-995; Rigotti et al., 1996, J. Biol. Chem.271:33545-33549). Other proposed HDL receptors include HB1 and HB2(Hidaka and Fidge, 1992, Biochem. J. 15:161-7; Kurata et al., 1998, J.Atherosclerosis and Thrombosis 4:112-7).

While there is a consensus that CETP is involved in the metabolism ofVLDL- and LDL-derived lipids, its role in RCT remains controversial.However, changes in CETP activity or its acceptors, VLDL and LDL, play arole in “remodeling” the HDL population. For example, in the absence ofCETP, the HDL becomes enlarged particles that are poorly removed fromthe circulation (for reviews on RCT and HDLs, see Fielding & Fielding,1995, J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys.Acta. 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol.17:1053-1059).

2.2.1. Reverse Transport of Other Lipids

HDL is not only involved in the reverse transport of cholesterol, butalso plays a role in the reverse transport of other lipids, i.e., thetransport of lipids from cells, organs, and tissues to the liver forcatabolism and excretion. Such lipids include sphingomyelin, oxidizedlipids, and lysophophatidylcholine. For example, Robins and Fasulo(1997, J. Clin. Invest. 99:380-384) have shown that HDL stimulates thetransport of plant sterol by the liver into bile secretions.

2.3. Peroxisome Proliferator Activated Receptor Pathway

Peroxisome proliferators are a structurally diverse group of compoundsthat, when administered to rodents, elicit dramatic increases in thesize and number of hepatic and renal peroxisomes, as well as concomitantincreases in the capacity of peroxisomes to metabolize fatty acids viaincreased expression of the enzymes required for the β-oxidation cycle(Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489-530; Vamecq andDraye, 1989, Essays Biochem. 24:1115-225; and Nelali et al., 1988,Cancer Res. 48:5316-5324). Chemicals included in this group are thefibrate class of hypolipidermic drugs, herbicides, and phthalateplasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1-58).Peroxisome proliferation can also be elicited by dietary orphysiological factors, such as a high-fat diet and cold acclimatization.

Insight into the mechanism whereby peroxisome proliferators exert theirpleiotropic effects was provided by the identification of a member ofthe nuclear hormone receptor superfamily activated by these chemicals(Isseman and Green, 1990, Nature 347:645-650). This receptor, termedperoxisome proliferator activated receptor α (PPAR_(α)), wassubsequently shown to be activated by a variety of medium and long-chainfatty acids. PPAR_(α) activates transcription by binding to DNA sequenceelements, termed peroxisome proliferator response elements (PPRE), inthe form of a heterodimer with the retinoid X receptor (RXR). RXR isactivated by 9-cis retinoic acid (see Kliewer et al., 1992, Nature358:771-774; Gearing et al., 1993, Proc. Natl. Acad. Sci. USA90:1440-1444, Keller et al., 1993, Proc. Natl. Acad. Sci. USA90:2160-2164; Heyman et al., 1992, Cell 68:397-406, and Levin et al.,1992, Nature 355:359-361). Since the discovery of PPAR_(α), additionalisoforms of PPAR have been identified, e.g., PPAR_(β), PPAR_(γ) andPPAR_(δ), which are have similar functions and are similarly regulated.

PPREs have been identified in the enhancers of a number of genesencoding proteins that regulate lipid metabolism. These proteins includethe three enzymes required for peroxisomal β-oxidation of fatty acids;apolipoprotein A-I; medium-chain acyl-CoA dehydrogenase, a key enzyme inmitochondrial β-oxidation; and aP2, a lipid binding protein expressedexclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM,4:291-296; see also Staels and Auwerx, 1998, Atherosclerosis 137Suppl:S19-23). The nature of the PPAR target genes coupled with theactivation of PPARs by fatty acids and hypolipidemic drugs suggests aphysiological role for the PPARs in lipid homeostasis.

Pioglitazone, an antidiabetic compound of the thiazolidinedione class,was reported to stimulate expression of a chimeric gene containing theenhancer/promoter of the lipid-binding protein aP2 upstream of thechloroamphenicol acetyl transferase reporter gene (Harris and Kletzien,1994, Mol. Pharmacol. 45:439-445). Deletion analysis led to theidentification of an approximately 30 bp region responsible forpioglitazone responsiveness. In an independent study, this 30 bpfragment was shown to contain a PPRE (Tontonoz et al., 1994, NucleicAcids Res. 22:5628-5634). Taken together, these studies suggested thepossibility that the thiazolidinediones modulate gene expression at thetranscriptional level through interactions with a PPAR and reinforce theconcept of the interrelatedness of glucose and lipid metabolism.

2.4. Current Cholesterol Management Therapies

In the past two decades or so, the segregation of cholesterolemiccompounds into HDL and LDL regulators and recognition of thedesirability of decreasing blood levels of the latter has led to thedevelopment of a number of drugs. However, many of these drugs haveundesirable side effects and/or are contraindicated in certain patients,particularly when administered in combination with other drugs.

Bile-acid-binding resins are a class of drugs that interrupt therecycling of bile acids from the intestine to the liver. Examples ofbile-acid-binding resins are cholestyramine (QUESTRAN LIGHT,Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia& Upjohn Company). When taken orally, these positively charged resinsbind to negatively charged bile acids in the intestine. Because theresins cannot be absorbed from the intestine, they are excreted,carrying the bile acids with them. The use of such resins, however, atbest only lowers serum cholesterol levels by about 20%. Moreover, theiruse is associated with gastrointestinal side-effects, includingconstipation and certain vitamin deficiencies. Moreover, since theresins bind to drugs, other oral medications must be taken at least onehour before or four to six hours subsequent to ingestion of the resin,complicating heart patients' drug regimens.

The statins are inhibitors of cholesterol synthesis. Sometimes, thestatins are used in combination therapy with bile-acid-binding resins.Lovastatin (MEVACOR, Merck & Co., Inc.), a natural product derived froma strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers SquibbCo.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterolsynthesis by inhibiting HMGCoA, the key enzyme involved in thecholesterol biosynthetic pathway. Lovastatin significantly reduces serumcholesterol and LDL-serum levels. It also slows progression of coronaryatherosclerosis. However, serum IDL levels are only slightly increasedfollowing lovastatin administration. The mechanism of the LDL-loweringeffect may involve both reduction of VLDL concentration and induction ofcellular expression of LDL-receptor, leading to reduced productionand/or increased catabolism of LDL. Side effects, including liver andkidney dysfunction are associated with the use of these drugs.

Niacin, also known as nicotinic acid, is a water-soluble vitaminB-complex used as a dietary supplement and antihyperlipidemic agent.Niacin diminishes production of VLDL and is effective at lowering LDL.It is used in combination with bile-acid-binding resins. Niacin canincrease HDL when administered at therapeutically effective doses;however, its usefulness is limited by serious side effects.

Fibrates are a class of lipid-lowering drugs used to treat various formsof hyperlipidemia, elevated serum triglycerides, which may also beassociated with hypercholesterolemia. Fibrates appear to reduce the VLDLfraction and modestly increase HDL; however, the effects of these drugson serum cholesterol is variable. In the United States, fibrates havebeen approved for use as antilipidemic drugs, but have not receivedapproval as hypercholesterolemia agents. For example, clofibrate(ATROMID-S, Wyeth-Ayerst Laboratories) is an antilipidemic agent thatacts to lower serum triglycerides by reducing the VLDL fraction.Although ATROMID-S may reduce serum cholesterol levels in certainpatient subpopulations, the biochemical response to the drug isvariable, and is not always possible to predict which patients willobtain favorable results. ATROMID-S has not been shown to be effectivefor prevention of coronary heart disease. The chemically andpharmacologically related drug, gemfibrozil (LOPID, Parke-Davis), is alipid regulating agent which moderately decreases serum triglyceridesand VLDL cholesterol. LOPID also increases HDL cholesterol, particularlythe HDL₂ and HDL₃ subfractions, as well as both the AI/AII-HDL fraction.However, the lipid response to LOPID is heterogeneous, especially amongdifferent patient populations. Moreover, while prevention of coronaryheart disease was observed in male patients between the ages of 40 and55 without history or symptoms of existing coronary heart disease, it isnot clear to what extent these findings can be extrapolated to otherpatient populations (e.g., women, older and younger males). Indeed, noefficacy was observed in patients with established coronary heartdisease. Serious side-effects are associated with the use of fibrates,including toxicity; malignancy, particularly malignancy ofgastrointestinal cancer; gallbladder disease; and an increased incidencein non-coronary mortality. These drugs are not indicated for thetreatment of patients with high LDL or low HDL as their only lipidabnormality.

Oral estrogen replacement therapy may be considered for moderatehypercholesterolemia in post-menopausal women. However, increases in HDLmay be accompanied with an increase in triglycerides. Estrogen treatmentis, of course, limited to a specific patient population, postmenopausalwomen, and is associated with serious side effects, including inductionof malignant neoplasms; gall bladder disease; thromboembolic disease;hepatic adenoma; elevated blood pressure; glucose intolerance; andhypercalcemia.

Long chain carboxylic acids, particularly long chain α,ω-dicarboxylicacids with distinctive substitution patterns, and their simplederivatives and salts, have been disclosed for treating atherosclerosis,obesity, and diabetes (See, e.g, Bisgaier et al., 1998, J. Lipid Res.39:17-30, and references cited therein; International Patent PublicationWO 98/30530; U.S. Pat. No. 4,689,344; International Patent PublicationWO 99/00116; and U.S. Pat. No. 5,756,344). However, some of thesecompounds, for example the α,ω-dicarboxylic acids substituted at theirα,α′-carbons (U.S. Pat. No. 3,773,946), while having serum triglycerideand serum cholesterol-lowering activities, have no value for treatmentof obesity and hypercholesterolemia (U.S. Pat. No. 4,689,344).

U.S. Pat. No. 4,689,344 disclosesβ,β,β′,β′-tetrasubstituted-α,ω-alkanedioic acids that are optionallysubstituted at their α,α,α′,α′ positions, and alleges that they areuseful for treating obesity, hyperlipidemia, and diabetes. According tothis reference, both triglycerides and cholesterol are loweredsignificantly by compounds Such as3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No. 4,689,344further discloses that the β,β,β′,β′-tetramethyl-alkanediols of U.S.Pat. No. 3,930,024 also are not useful for treating hypercholesterolemiaor obesity.

Other compounds are disclosed in U.S. Pat. No. 4,711,896. In U.S. Pat.No. 5,756,544, α,ω-dicarboxylic acid-terminated dialkane ethers aredisclosed to have activity in lowering certain plasma lipids, includingLp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, in animals,and elevating others, such as HDL-cholesterol. The compounds are alsostated to increase insulin sensitivity. In U.S. Pat. No. 4,613,593,phosphates of dolichol, a polyprenol isolated from swine liver, arestated to be useful in regenerating liver tissue, and in treatinghyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.

U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives withanti-diabetic, hypolipidemic, and anti-hypertensive properties. However,these administration of these compounds to patients can produce sideeffects such as bone marrow depression, and both liver and cardiaccytotoxicity. Further, the compounds disclosed by U.S. Pat. No.4,287,200 stimulate weight gain in obese patients.

It is clear that none of the commercially available cholesterolmanagement drugs has a general utility in regulating lipid, lipoprotein,insulin and glucose levels in the blood. Thus, compounds that have oneor more of these utilities are clearly needed. Further, there is a clearneed to develop safer drugs that are efficacious at lowering serumcholesterol, increasing HDL serum levels, preventing coronary heartdisease, and/or treating existing disease such as atherosclerosis,obesity, diabetes, and other diseases that are affected by lipidmetabolism and/or lipid levels. There is also is a clear need to developdrugs that may be used with other lipid-altering treatment regimens in asynergistic manner. There is still a further need to provide usefultherapeutic agents whose solubility and Hydrophile/Lipophile Balance(HLB) can be readily varied.

Citation or identification of any reference in Section 2 of thisapplication is not an admission that such reference is available asprior art to the present invention.

3. SUMMARY OF THE INVENTION

In one embodiment, the invention provides novel compounds having thegeneral formula I:

and pharmaceutically acceptable salts thereof, wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently selected from the group consisting of—CH₂OH, —C(O)OH, —CHO, —C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

In another embodiment, the invention provides novel compounds having thegeneral formula I, and pharmaceutically acceptable salts thereof,wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently selected from the group consisting of—CH₂OH, —C(O)OH, —CHO, —C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R⁵ is selected from the group consisting Of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

In yet another embodiment, the invention provides novel compounds havingthe general formula I, and pharmaceutically acceptable salts thereof,wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ is selected from the group consisting of —CH₂OH, —OC(O)R⁵, —CHO,—SO₃H,

K² is selected from the group consisting of —CH₂OH, —C(O)OH, CHO,—C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

In yet another embodiment, the invention provides novel compounds havingthe general formula I and pharmaceutically acceptable salts thereof,wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently selected from the group consisting of—CH₂OH, —OC(O)R⁵, —CHO, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

In still another embodiment, the invention provides novel compoundshaving the general formula 1, and pharmaceutically acceptable saltsthereof, wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently —CH₂OH or —OC(O)R⁵; and

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl.

The compounds of formula I and pharmaceutically acceptable salts thereofare useful for treating or preventing cardiovascular diseases,dyslipidemias, dyslipoproteinemias, disorders of glucose metabolism,Alzheimer's Disease, Syndrome X, PPAR-associated disorders, septicemia,thrombotic disorders, obesity, pancreatitis, hypertension, renaldiseases, cancer, inflammation, or impotence.

In another embodiment, the invention comprises a compound of the formulaIV:

wherein:

n is an integer ranging from 1 to 4;

K¹ selected from the group consisting of —CH₂OH, —C(O)OH, —CHO,—C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R¹ and R² are independently selected from the group consisting of(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; or R¹,R², and the carbon to which they are attached are taken together to forma (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₇)cycloalkyl group; or R¹,R², and the carbon to which they are attached are taken together to forma (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₇)cycloalkyl group, with theproviso that none of R¹, R², R³, or R⁴ is (CH₂)₀₋₄C≡CH;

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

W is selected from the group consisting of H, (C₁-C₆)alkyl, and ahydroxy protecting group.

In another embodiment, the invention provides a compound of the formulaV:

wherein:

n is an integer ranging from 1 to 4;

K¹ selected from the group consisting of —CH₂OH, —C(O)OH, —CHO,—C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R³, and R⁴ are independently selected from the group consisting of(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; or R¹,R², and the carbon to which they are attached are taken together to forma (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₇)cycloalkyl group; or R¹,R², and the carbon to which they are attached are taken together to forma (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₇)cycloalkyl group, with theproviso that none of R¹, R², R³, or R⁴ is (CH₂) 4C═CH;

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H,(C₁-C₆)alkyl,(C₂-C₆)alkenyl, and C₂-C₆)alkynyl; and

Hal is selected from the group consisting of chloro, bromo, and iodo.

The compounds of formulas IV and V are useful as intermediates forsynthesizing the compounds of formula I.

In still another embodiment, the invention provides a method for thesynthesis of a compound of a formula II:

comprising (a) contacting in the presence of a base a compound of aformula XXIV:

with a compound of a formula XXVIII:

to provide a compound of a formula XXIX:

and (b) deprotecting the compound of the formula XXIX to provide thecompound of the formula II, wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH; and

PG is a hydroxy protecting group.

In still another embodiment, the invention provides a method for thesynthesis of a compound of formula III:

comprising contacting a compound of a formula of formula VI:

with a reducing agent, wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

each R¹⁰ is independently selected from the group consisting of —H, —OH,(C₁-C₈)alkoxy, (C₆)aryloxy, —O—(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, halo;and

n and m are independent integers ranging from 0 to 4.

The present invention further provides compositions comprising acompound of the formula I or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable vehicle. These compositions are usefulfor treating or preventing a disease or disorder selected from the groupconsisting of a cardiovascular disease, dyslipidemia,dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer'sDisease, Syndrome X, a PPAR-associated disorder, septicemia, athrombotic disorder, obesity, pancreatitis, hypertension, a renaldisease, cancer, inflammation, and impotence. These composition are alsouseful for reducing the fat content of meat in livestock and reducingthe cholesterol content of eggs.

The present invention provides a method for treating or preventing acardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder ofglucose metabolism, Alzheimer's Disease, Syndrome X, a PPAR-associateddisorder, septicemia, a thrombotic disorder, obesity, pancreatitis,hypertension, a renal disease, cancer, inflammation, and impotence,comprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a compositioncomprising a compound of formula I, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable vehicle.

The present invention further provides a method for reducing the fatcontent of meat in livestock comprising administering to livestock inneed of such fat-content reduction a therapeutically effective amount ofa composition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable vehicle.

The present invention provides a method for reducing the cholesterolcontent of a fowl egg comprising administering to a fowl species atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable vehicle.

The present invention may be understood more fully by reference to thefigures, detailed description, and examples, which are intended toexemplify non-limiting embodiments of the invention.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the serum cholesterol profiles of Male Sprague-Dawley ratsfollowing one week of treatment with Compound A.

FIG. 2 shows the lipid and lipoprotein levels of Male Sprague-Dawleyrats following one week of treatment with Compound A.

FIG. 3 shows the apolipoprotein levels of Male Sprague-Dawley ratsfollowing one week of treatment with Compound A.

FIG. 4 shows the percentage weight gain of Male Sprague-Dawley ratsfollowing one week of treatment with Compound A.

FIG. 5 shows the effect on serum cholesterol and triglyceride levels inobese female Zucker rats following one week of treatment with Compound Aor troglitazone.

FIG. 6 shows the effect on serum lipoprotein cholesterol profile inobese female Zucker rats following one week of treatment with Compound Aor troglitazone.

FIG. 7 shows the total VLDL and LDL, total HDL, and the HDL:(VLDL+LDL)ratio following one week of Compound A or troglitazone treatment ofobese female Zucker rats.

FIG. 8 shows serum glucose and non-esterified fatty acid levels of obesefemale Zucker rats following one week of Compound A or troglitazonetreatment.

FIG. 9 shows the percentage weight gain of obese female Zucker ratsfollowing one week of Compound A or troglitazone treatment.

FIG. 10 shows the amount and percentage reduction of serum triglyceridesin obese female Zucker rats following 1- and 2-week treatment withCompound A or troglitazone.

FIG. 11 shows the effect of Compound A or troglitazone treatment ofobese female Zucker rats on HDL, LDL and total serum total cholesterol.

FIG. 12 shows the effect of Compound A or troglitazone on the bloodglucose of obese female Zucker rats.

FIG. 13 shows the effect of Compound A or troglitazone on the seruminsulin levels of obese female Zucker.

FIG. 14 shows the effect of Compound A or troglitazone on the glucose toinsulin ratio in obese female Zucker rats.

FIG. 15 shows the weekly percent weight gain in the Zucker rats duringtreatment with Compound A or troglitazone.

FIG. 16 shows the percent liver to body weight ratio in obese femaleZucker rats after two weeks of treatment with Compound A ortroglitazone.

FIG. 17 shows the effect on the serum lipoprotein cholesterol profile ofLDL receptor deficient mice following seven daily treatments withCompound A.

FIG. 18 shows the rates of synthesis of non-saponified and saponifiedlipid in primary rat hepatocytes upon treatment with Compound A,Compound B, Compound D, Compound E, Compound F, or lovastatin.

FIG. 19 shows the ratio of LDH leakage in primary rat hepatocytescontacted in vitro with increasing concentrations of Compounds A, B, C,or D during a 24 hr period.

FIG. 20 shows the insulin sensitizing effects of Compound A on culturedpreadipocytes.

5. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds having the generalformula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently selected from the group consisting of—CH₂OH, —C(O)OH, —CHO, —C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆) alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

The compounds of formula I and pharmaceutically acceptable salts thereofare useful for treating or preventing cardiovascular diseases,dyslipidemias, dyslipoproteinemias, disorders of glucose metabolism,Alzheimer's Disease, Syndrome X, PPAR-associated disorders, septicemia,thrombotic disorders, obesity, pancreatitis, hypertension, renaldiseases, cancer, inflammation, or impotence. In this regard, thecompounds of formula I are particularly useful when incorporated in acomposition. A composition of the invention need not contain aningredient, including an exicpient, other than a compound of theinvention. Accordingly, in one embodiment, the compositions of theinvention can omit a pharmaceutically acceptable vehicle. Accordingly,the present invention provides methods for treating or preventingcardiovascular diseases, dyslipidemias, dyslipoproteinemias, disordersof glucose metabolism, Alzheimer's Disease, Syndrome X, PPAR-associateddisorders, septicemia, thrombotic disorders, obesity, pancreatitis,hypertension, renal diseases, cancer, inflammation, or impotence,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a composition comprising a compound of formula I ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable vehicle.

In certain embodiments of the invention, a compound of formula I or apharmaceutically acceptable salt thereof is administered in combinationwith another therapeutic agent. The other therapeutic agent providesadditive or synergistic value relative to the administration of acompound of formula I alone. The therapeutic agent can be a statin; aPPAR agonist, e.g., a thiazolidinedione or fibrate; abile-acid-binding-resin; a niacin; a RXR agonist; an anti-obesity drug;a hormone; a tyrophostine; a sulfonylurea-based drug; a biguanide; anα-glucosidase inhibitor; an apolipoprotein A-I agonist; apolipoproteinE; a cardiovascular drug; an HDL-raising drug; an HDL enhancer; or aregulator of the apolipoprotein A-I, apolipoprotein A-IV and/orapolipoprotein genes.

The present invention further encompasses compositions comprising apharmaceutically acceptable vehicle; and a compound of formula I or apharmaceutically acceptable salt thereof.

Preferably, the compounds of formula I and pharmaceutically acceptablesalts thereof, are those wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently selected from the group consisting of—CH₂OH, —C(O)OH, —CHO, —C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

More preferably, the compounds of formula I and pharmaceuticallyacceptable salts thereof, are those wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ is selected from the group consisting of —CH₂OH, —OC(O)R⁵, —CHO,—SO₃H,

K² is selected from the group consisting of —CH₂OH, —C(O)OH, —CHO,—C(O)OR⁵, —OC(O)R⁵, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

Still more preferably, the compounds of formula I and pharmaceuticallyacceptable salts thereof, are those wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently selected from the group consisting of—CH₂OH, —OC(O)R⁵, —CHO, —SO₃H,

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl;

each R⁶ is independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl;

R⁷ is selected from the group consisting of H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; and

with the proviso that when n and m are both 1 or both 0, then K¹ and K²are not both X, wherein X is selected from the group consisting of—COOH, —C(O)OR⁵,

Still more preferably, the compounds of formula I and pharmaceuticallyacceptable salts thereof, are those wherein:

R¹, R², R³, and R⁴ are independently selected from the group consistingof (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group; orR¹, R², and the carbon to which they are attached are taken together toform a (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which theyare attached are taken together to form a (C₃-C₇)cycloalkyl group, withthe proviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH;

n and m are independent integers ranging from 0 to 4;

K¹ and K² are independently —CH₂OH or —OC(O)R⁵; and

R⁵ is selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl.

Preferred compounds of formula I are selected from the group consistingof:

2,2-diethyl-6-(5-ethyl-5-hydroxymethyl-heptyloxy)-hexan-1-ol;

7-(5,5-diethyl-7-hydroxy-heptyloxy)-3,3-diethyl-heptan-1-ol;

2,2-diethyl-6-(5-ethyl-5-hydroxymethyl-heptyloxy)-hexanoic acid;

3,3-diethyl-7-(5-ethyl-5-hydroxymethyl-heptyloxy)-heptanoic acid;

6-(5,5-diethyl-7-hydroxy-heptyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-7-hydroxy-heptyloxy)-3,3-diethyl-heptanoic acid;

6-(5,5-diethyl-8-hydroxy-octyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-8-hydroxy-octyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-8-hydroxy-octyloxy)-4,4-diethyl-octanoic acid;

6-(5,5-diethyl-9-hydroxy-nonyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-9-hydroxy-nonyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-9-hydroxy-nonyloxy)-4,4-diethyl-octanoic acid;

9-(5,5-diethyl-9-hydroxy-nonyloxy)-5,5-diethyl-nonanoic acid;

6-(5,5-diethyl-10-hydroxy-decyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-10-hydroxy-decyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-10-hydroxy-decyloxy)-4,4-diethyl-octanoic acid;

9-(5,5-diethyl-10-hydroxy-decyloxy)-5,5-diethyl-nonanoic acid;

10-(5,5-diethyl-10-hydroxy-decyloxy)-6,6-diethyl-decanoic acid;

phosphoric acidmono-[1,1-diethyl-5-(5-ethyl-5-hydroxymethyl-heptyloxy)-pentyl] ester;

phosphoric acidmono-[2,2-diethyl-6-(5-ethyl-5-hydroxymethyl-heptyloxy)-hexyl] ester;

phosphoric acidmono-[5-(5,5-diethyl-7-hydroxy-heptyloxy)-1,1-diethyl-pentyl] ester;

phosphoric acidmono-[6-(5,5-diethyl-7-hydroxy-heptyloxy)-2,2-diethyl-hexyl] ester;

phosphoric acidmono-[5-(5,5-diethyl-8-hydroxy-octyloxy)-1,1-diethyl-pentyl] ester;

phosphoric acidmono-[6-(5,5-diethyl-8-hydroxy-octyloxy)-2,2-diethyl-hexyl] ester;

phosphoric acidmono-[7-(5,5-diethyl-8-hydroxy-octyloxy)-3,3-diethyl-heptyl] ester;

phosphoric acidmono-[5-(5,5-diethyl-9-hydroxy-nonyloxy)-1,1-diethyl-pentyl] ester;

phosphoric acidmono-[6-(5,5-diethyl-9-hydroxy-nonyloxy)-2,2-diethyl-hexyl] ester;

phosphoric acidmono-[7-(5,5-diethyl-9-hydroxy-nonyloxy)-3,3-diethyl-heptyl] ester;

phosphoric acidmono-[8-(5,5-diethyl-9-hydroxy-nonyloxy)-4,4-diethyl-octyl] ester;

phosphoric acidmono-[5-(5,5-diethyl-10-hydroxy-decyloxy)-1,1-diethyl-pentyl] ester;

phosphoric acidmono-[6-(5,5-diethyl-10-hydroxy-decyloxy)-2,2-diethyl-heptyl] ester;

phosphoric acidmono-[7-(5,5-diethyl-10-hydroxy-decyloxy)-3,3-diethyl-heptyl] ester;

phosphoric acidmono-[8-(5,5-diethyl-10-hydroxy-decyloxy)-4,4-diethyl-octyl] ester;

phosphoric acidmono-[9-(5,5-diethyl-10-hydroxy-decyloxy)-5,5-diethyl-nonyl] ester;

2,2-diethyl-6-(5-ethyl-5-phosphonooxy-heptyloxy)-hexanoic acid;

3,3-diethyl-7-(5-ethyl-5-phosphonooxy-heptyloxy)-heptanoic acid;

2,2-diethyl-6-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-hexanoic acid;

3,3-diethyl-7-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-heptanoic acid;

6-(5,5-diethyl-7-phosphonooxy-heptyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-7-phosphonooxy-heptyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-7-phosphonooxy-heptyloxy)-4,4-diethyl-octanoic acid;

6-(5,5-diethyl-8-phosphonooxy-octyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-8-phosphonooxy-octyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-8-phosphonooxy-octyloxy)-4,4-diethyl-octanoic acid;

9-(5,5-diethyl-8-phosphonooxy-octyloxy)-5,5-diethyl-nonanoic acid;

6-(5,5-diethyl-9-phosphonooxy-nonyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-9-phosphonooxy-nonyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-9-phosphonooxy-nonyloxy)-4,4-diethyl-octanoic acid;

9-(5,5-diethyl-9-phosphonooxy-nonyloxy)-5,5-diethyl-nonanoic acid;

10-(5,5-diethyl-9-phosphonooxy-nonyloxy)-6,6-diethyl-decanoic acid;

phosphoric acidmono-[1,1-diethyl-5-(5-ethyl-5-phosphonooxy-heptyloxy)-pentyl] ester;

phosphoric acidmono-[1,2-diethyl-5-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-pentyl]ester;

phosphoric acidmono-[2,2-diethyl-6-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-hexyl]ester;

phosphoric acidmono-[3,3-diethyl-7-(5-ethyl-5-phosphonooxy-heptyloxy)-heptyl] ester;

phosphoric acidmono-[3,3-diethyl-7-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-heptyl]ester;

phosphoric acidmono-[7-(5,5-diethyl-7-phosphonooxy-heptyloxy)-3,3-diethyl-heptyl]ester;

phosphoric acidmono-[4,4-diethyl-8-(5-ethyl-5-phosphonooxy-heptyloxy)-octyl] ester;

phosphoric acidmono-[4,4-diethyl-8-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-octyl]ester;

phosphoric acidmono-[8-(5,5-diethyl-7-phosphonooxy-heptyloxy)-4,4-diethyl-octyl] ester;

phosphoric acidmono-[8-(5,5-diethyl-8-phosphonooxy-octyloxy)-4,4-diethyl-octyl] ester;

phosphoric acidmono-[5,5-diethyl-9-(5-ethyl-5-phosphonooxy-heptyloxy)-nonyl] ester;

phosphoric acidmono-[5,5-diethyl-9-(5-ethyl-5-phosphonooxymethyl-heptyloxy)-nonyl]ester;

phosphoric acidmono-[9-(5,5-diethyl-7-phosphonooxy-heptyloxy)-5,5-diethyl-nonyl] ester;

phosphoric acidmono-[9-(5,5-diethyl-8-phosphonooxy-octyloxy)-5,5-diethyl-nonyl] ester;

phosphoric acidmono-[9-(5,5-diethyl-9-phosphonooxy-nonyloxy)-5,5-diethyl-nonyl] ester;

6-(6-hydroxy-5,5-diethyl-hexyloxy)-3-ethyl-heptane-2-sulfonic acidamide;

6-(6-hydroxy-5,5-diethyl-hexyloxy)-2,2-diethyl-hexane-1-sulfonic acidamide;

6-(7-hydroxy-5,5-diethyl-heptyloxy)-3-ethyl-heptane-2-sulfonic acidamide;

6-(7-hydroxy-5,5-diethyl-heptyloxy)-2,2-diethyl-hexane-1-sulfonic acidamide;

7-(5,5-diethyl-8-hydroxy-octyloxy)-3-ethyl-heptane-3-sulfonic acidamide;

6-(5,5-diethyl-8-hydroxy-octyloxy)-2,2-diethyl-hexane-1-sulfonic acidamide;

7-(5,5-diethyl-8-hydroxy-octyloxy)-3,3-diethyl-heptane-1-sulfonic acidamide;

7-(5,5-diethyl-9-hydroxy-nonyloxy)-3-ethyl-heptane-3-sulfonic acidamide;

6-(5,5-diethyl-9-hydroxy-nonyloxy)-2,2-diethyl-hexane-1-sulfonic acidamide;

7-(5,5-diethyl-9-hydroxy-nonyloxy)-3,3-diethyl-heptane-1-sulfonic acidamide;

8-(5,5-diethyl-9-hydroxy-nonyloxy)-4,4-diethyl-octane-1-sulfonic acidamide;

7-(5,5-diethyl-10-hydroxy-decyloxy)-3-ethyl-heptane-3-sulfonic acidamide;

6-(5,5-diethyl-10-hydroxy-decyloxy)-2,2-diethyl-hexane-1-sulfonic acidamide;

7-(5,5-diethyl-10-hydroxy-decyloxy)-3,3-diethyl-heptane-1-sulfonic acidamide;

8-(5,5-diethyl-10-hydroxy-decyloxy)-4,4-diethyl-octane-1-sulfonic acidamide;

9-(5,5-diethyl-10-hydroxy-decyloxy)-5,5-diethyl-nonane-1-sulfonic acidamide;

2,2-diethyl-6-(5-ethyl-5-sulfamoyl-heptyloxy)-hexanoic acid;

3,3-diethyl-7-(5-ethyl-5-sulfamoyl-heptyloxy)-heptanoic acid;

2,2-diethyl-6-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-hexanoic acid;

3,3-diethyl-7-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-heptanoic acid;

6-(5,5-diethyl-7-sulfamoyl-heptyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-7-sulfamoyl-heptyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-7-sulfamoyl-heptyloxy)-4,4-diethyl-octanoic acid;

6-(5,5-diethyl-8-sulfamoyl-octyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-8-sulfamoyl-octyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-8-sulfamoyl-octyloxy)-4,4-diethyl-octanoic acid;

9-(5,5-diethyl-8-sulfamoyl-octyloxy)-5,5-diethyl-nonanoic acid,

6-(5,5-diethyl-9-sulfamoyl-nonyloxy)-2,2-diethyl-hexanoic acid;

7-(5,5-diethyl-9-sulfamoyl-nonyloxy)-3,3-diethyl-heptanoic acid;

8-(5,5-diethyl-9-sulfamoyl-nonyloxy)-4,4-diethyl-octanoic acid;

9-(5,5-diethyl-9-sulfamoyl-nonyloxy)-5,5-diethyl-nonanoic acid;

10-(5,5-diethyl-9-sulfamoyl-nonyloxy)-6,6-diethyl-decanoic acid;

3-ethyl-7-(5-ethyl-5-sulfamoyl-heptyloxy)-heptane-3-sulfonic acid amide;

3-ethyl-7-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-heptane-3-sulfonic acidamide;

2,2-diethyl-6-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-hexane-1-sulfonicacid amide;

3,3-diethyl-7-(5-ethyl-5-sulfamoyl-heptyloxy)-heptane-1-sulfonic acidamide;

3,3-diethyl-7-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-heptane-1-sulfonicacid amide;

7-(5,5-diethyl-7-sulfamoyl-heptyloxy)-3,3-diethyl-heptane-1-sulfonicacid amide;

4,4-diethyl-8-(5-ethyl-5-sulfamoyl-heptyloxy)-octane-1-sulfonic acidamide;

4,4-diethyl-8-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-octane-1-sulfonicacid amide;

8-(5,5-diethyl-7-sulfamoyl-heptyloxy)-4,4-diethyl-octane-1-sulfonic acidamide;

8-(5,5-diethyl-8-sulfamoyl-octyloxy)-4,4-diethyl-octane-1-sulfonic acidamide;

5,5-diethyl-9-(5-ethyl-5-sulfamoyl-heptyloxy)-nonane-1-sulfonic acidamide;

5,5-diethyl-9-(5-ethyl-5-sulfamoylmethyl-heptyloxy)-nonane-1-sulfonicacid amide;

9-(5,5-diethyl-7-sulfamoyl-heptyloxy)-5,5-diethyl-nonane-1-sulfonic acidamide;

9-(5,5-diethyl-8-sulfamoyl-octyloxy)-5,5-diethyl-nonane-1-sulfonic acidamide;

9-(5,5-diethyl-9-sulfamoyl-nonyloxy)-5,5-diethyl-nonane-1-sulfonic acidamide;

3-[1,1-diethyl-5-(5-ethyl-5-hydroxymethyl-heptyloxy)-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[2,2-diethyl-6-(5-ethyl-5-hydroxymethyl-heptyloxy)-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(5,5-diethyl-7-hydroxy-heptyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(5,5-diethyl-7-hydroxy-heptyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(5,5-diethyl-8-hydroxy-octyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(5,5-diethyl-8-hydroxy-octyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(5,5-diethyl-8-hydroxy-octyloxy)-3,3-diethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(5,5-diethyl-9-hydroxy-nonyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(5,5-diethyl-9-hydroxy-nonyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(5,5-diethyl-9-hydroxy-nonyloxy)-3,3-diethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[8-(5,5-diethyl-9-hydroxy-nonyloxy)-4,4-diethyl-octyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(5,5-diethyl-10-hydroxy-decyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(5,5-diethyl-10-hydroxy-decyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(5,5-diethyl-10-hydroxy-decyloxy)-3,3-diethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[8-(5,5-diethyl-10-hydroxy-decyloxy)-4,4-diethyl-octyl]-1-ethyl-imidazolidine-2,4-dione;

3-[9-(5,5-diethyl-10-hydroxy-decyloxy)-5,5-diethyl-nonyl]-1-ethyl-imidazolidine-2,4-dione;

2,2-diethyl-6-[5-ethyl-5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-heptyloxy]-hexanoicacid;

3,3-diethyl-7-[5-ethyl-5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-heptyloxy]-heptanoicacid;

2-diethyl-6-[5-ethyl-5-(3-ethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-heptyloxy]-hexanoicacid;

3-diethyl-7-[5-ethyl-5-(3-ethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-heptyloxy]-heptanoicacid;

6-[5,5-diethyl-7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-heptyloxy]-2,2-diethyl-hexanoicacid;

7-[5,5-diethyl-7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-heptyloxy]-3,3-diethyl-heptanoicacid;

8-[5,5-diethyl-7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-heptyloxy]-4,4-diethyl-octanoicacid;

6-[5,5-diethyl-8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-octyloxy]-2,2-diethyl-hexanoicacid;

7-[5,5-diethyl-8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-octyloxy]-3,3-diethyl-heptanoicacid;

8-[5,5-diethyl-8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-octyloxy]-4,4-diethyl-octanoicacid;

9-[5,5-diethyl-8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-octyloxy]-5,5-diethyl-nonanoicacid;

6-[5,5-diethyl-9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-nonyloxy]-2,2-diethyl-hexanoicacid;

7-[5,5-diethyl-9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-nonyloxy]-3,3-diethyl-heptanoicacid;

8-[5,5-diethyl-9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-nonyloxy]-4,4-diethyl-octanoicacid;

9-[5,5-diethyl-9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-nonyloxy]-5,5-diethyl-nonanoicacid;

10-[5,5-diethyl-9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-nonyloxy]-6,6-diethyl-decanoicacid;

3-[5-(5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5-ethyl-heptyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-methyl-5-ethyl-heptyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-methyl-5-ethyl-heptyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-heptyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-heptyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-heptyloxy)-3,3-diethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-octyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-octyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-octyloxy)-3,3-diethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[8-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-octyloxy)-4,4-diethyl-octyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-nonyloxy)-1,1-diethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-nonyloxy)-2,2-diethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-nonyloxy)-3,3-diethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[8-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-nonyloxy)-4,4-diethyl-octyl]-1-ethyl-imidazolidine-2,4-dione;

3-[9-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-diethyl-nonyloxy)-5,5-diethyl-nonyl]-1-ethyl-imidazolidine-2,4-dione;

6-(6-hydroxy-5,5-dimethyl-hexyloxy)-2,2-dimethyl-hexan-1-ol;

7-(7-hydroxy-5,5-dimethyl-heptyloxy)-3,3-dimethyl-heptan-1-ol;

6-(6-hydroxy-5,5-dimethyl-hexyloxy)-2,2-dimethyl-hexanoic acid;

7-(6-hydroxy-5,5-dimethyl-hexyloxy)-3,3-dimethyl-heptanoic acid;

6-(7-hydroxy-5,5-dimethyl-heptyloxy)-2,2-dimethyl-hexanoic acid;

7-(7-hydroxy-5,5-dimethyl-heptyloxy)-3,3-dimethyl-heptanoic acid;

6-(8-hydroxy-5,5-dimethyl-octyloxy)-2,2-dimethyl-hexanoic acid;

7-(8-hydroxy-5,5-dimethyl-octyloxy)-3,3-dimethyl-heptanoic acid;

8-(8-hydroxy-5,5-dimethyl-octyloxy)-4,4-dimethyl-octanoic acid;

6-(9-hydroxy-5,5-dimethyl-nonyloxy)-2,2-dimethyl-hexanoic acid;

7-(9-hydroxy-5,5-dimethyl-nonyloxy)-3,3-dimethyl-heptanoic acid;

8-(9-hydroxy-5,5-dimethyl-nonyloxy)-4,4-dimethyl-octanoic acid;

9-(9-hydroxy-5,5-dimethyl-nonyloxy)-5,5-dimethyl-nonanoic acid;

6-(10-hydroxy-5,5-dimethyl-decyloxy)-2,2-dimethyl-hexanoic acid;

7-(10-hydroxy-5,5-dimethyl-decyloxy)-3,3-dimethyl-heptanoic acid;

8-(10-hydroxy-5,5-dimethyl-decyloxy)-4,4-dimethyl-octanoic acid;

9-(10-hydroxy-5,5-dimethyl-decyloxy)-5,5-dimethyl-nonanoic acid;

10-(10-hydroxy-5,5-dimethyl-decyloxy)-6,6-dimethyl-decanoic acid;

phosphoric acidmono-[5-(6-hydroxy-5,5-dimethyl-hexyloxy)-1,1-dimethyl-pentyl] ester;

phosphoric acidmono-[6-(6-hydroxy-5,5-dimethyl-hexyloxy)-2,2-dimethyl-hexyl] ester;

phosphoric acidmono-[5-(7-hydroxy-5,5-dimethyl-heptyloxy)-1,1-dimethyl-pentyl] ester;

phosphoric acidmono-[6-(7-hydroxy-5,5-dimethyl-heptyloxy)-2,2-dimethyl-hexyl] ester;

phosphoric acidmono-[5-(8-hydroxy-5,5-dimethyl-octyloxy)-1,1-dimethyl-pentyl] ester;

phosphoric acidmono-[6-(8-hydroxy-5,5-dimethyl-octyloxy)-2,2-dimethyl-hexyl] ester;

phosphoric acidmono-[7-(8-hydroxy-5,5-dimethyl-octyloxy)-3,3-dimethyl-heptyl] ester;

phosphoric acidmono-[5-(9-hydroxy-5,5-dimethyl-nonyloxy)-1,1-dimethyl-pentyl] ester;

phosphoric acidmono-[6-(9-hydroxy-5,5-dimethyl-nonyloxy)-2,2-dimethyl-hexyl] ester;

phosphoric acidmono-[7-(9-hydroxy-5,5-dimethyl-nonyloxy)-3,3-dimethyl-heptyl] ester;

phosphoric acidmono-[8-(9-hydroxy-5,5-dimethyl-nonyloxy)-4,4-dimethyl-octyl] ester;

phosphoric acidmono-[5-(10-hydroxy-5,5-dimethyl-decyloxy)-1,1-dimethyl-pentyl] ester;

phosphoric acidmono-[6-(10-hydroxy-5,5-dimethyl-decyloxy)-2,2-dimethyl-hexyl] ester;

phosphoric acidmono-[7-(10-hydroxy-5,5-dimethyl-decyloxy)-3,3-dimethyl-heptyl] ester;

phosphoric acidmono-[8-(10-hydroxy-5,5-dimethyl-decyloxy)-4,4-dimethyl-octyl] ester;

phosphoric acidmono-[9-(10-hydroxy-5,5-dimethyl-decyloxy)-5,5-dimethyl-nonyl] ester;

2,2-dimethyl-6-(5-methyl-5-phosphonooxy-hexyloxy)-hexanoic acid;

3,3-dimethyl-7-(5-methyl-5-phosphonooxy-hexyloxy)-heptanoic acid;

6-(5,5-dimethyl-6-phosphonooxy-hexyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-6-phosphonooxy-hexyloxy)-3,3-dimethyl-heptanoic acid;

6-(5,5-dimethyl-7-phosphonooxy-heptyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-7-phosphonooxy-heptyloxy)-3,3-dimethyl-heptanoic acid;

8-(5,5-dimethyl-7-phosphonooxy-heptyloxy)-4,4-dimethyl-octanoic acid;

6-(5,5-dimethyl-8-phosphonooxy-octyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-8-phosphonooxy-octyloxy)-3,3-dimethyl-heptanoic acid;

8-(5,5-dimethyl-8-phosphonooxy-octyloxy)-4,4-dimethyl-octanoic acid;

9-(5,5-dimethyl-8-phosphonooxy-octyloxy)-5,5-dimethyl-nonanoic acid;

6-(5,5-dimethyl-9-phosphonooxy-nonyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-9-phosphonooxy-nonyloxy)-3,3-dimethyl-heptanoic acid;

8-(5,5-dimethyl-9-phosphonooxy-nonyloxy)-4,4-dimethyl-octanoic acid;

9-(5,5-dimethyl-9-phosphonooxy-nonyloxy)-5,5-dimethyl-nonanoic acid;

10-(5,5-dimethyl-9-phosphonooxy-nonyloxy)-6,6-dimethyl-decanoic acid;

phosphoric acidmono-[1,1-dimethyl-5-(5-methyl-5-phosphonooxy-hexyloxy)-pentyl] ester;

phosphoric acidmono-[2,2-dimethyl-6-(5-methyl-5-phosphonooxy-hexyloxy)-hexyl] ester;

phosphoric acidmono-[6-(5,5-dimethyl-6-phosphonooxy-hexyloxy)-2,2-dimethyl-hexyl]ester;

phosphoric acidmono-[3,3-dimethyl-7-(5-methyl-5-phosphonooxy-hexyloxy)-heptyl] ester;

phosphoric acidmono-[7-(5,5-dimethyl-6-phosphonooxy-hexyloxy)-3,3-dimethyl-heptyl]ester;

phosphoric acidmono-[7-(5,5-dimethyl-7-phosphonooxy-heptyloxy)-3,3-dimethyl-heptyl]ester;

phosphoric acidmono-[4,4-dimethyl-8-(5-methyl-5-phosphonooxy-hexyloxy)-octyl] ester;

phosphoric acidmono-[8(5,5-dimethyl-6-phosphonooxy-hexyloxy)-4,4-dimethyl-octyl] ester;

phosphoric acidmono-[8-(5,5-dimethyl-7-phosphonooxy-heptyloxy)-4,4-dimethyl-octyl]ester;

phosphoric acidmono-[8-(5,5-dimethyl-8-phosphonooxy-octyloxy)-4,4-dimethyl-octyl]ester;

phosphoric acidmono-[5,5-dimethyl-9-(5-methyl-5-phosphonooxy-hexyloxy-nonyl] ester;

phosphoric acidmono-[9-(5,5-dimethyl-6-phosphonooxy-hexyloxy)-5,5-dimethyl-nonyl]ester;

phosphoric acidmono-[9-(5,5-dimethyl-7-phosphonooxy-heptyloxy)-5,5-dimethyl-nonyl]ester;

phosphoric acidmono-[9-(5,5-dimethyl-8-phosphonooxy-octyloxy)-5,5-dimethyl-nonyl]ester;

phosphoric acidmono-[9-(5,5-dimethyl-9-phosphonooxy-nonyloxy)-5,5-dimethyl-nonyl]ester;

6-(6-hydroxy-5,5-dimethyl-hexyloxy)-2-methyl-hexane-2-sulfonic acidamide;

6-(6-hydroxy-5,5-dimethyl-hexyloxy)-2,2-dimethyl-hexane-1-sulfonic acidamide;

6-(7-hydroxy-5,5-dimethyl-heptyloxy)-2-methyl-hexane-2-sulfonic acidamide;

6-(7-hydroxy-5,5-dimethyl-heptyloxy)-2,2-dimethyl-hexane-1-sulfonic acidamide;

6-(8-hydroxy-5,5-dimethyl-octyloxy)-2-methyl-hexane-2-sulfonic acidamide;

6-(8-hydroxy-5,5-dimethyl-octyloxy)-2,2-dimethyl-hexane-1-sulfonic acidamide;

7-(8-hydroxy-5,5-dimethyl-octyloxy)-3,3-dimethyl-heptane-1-sulfonic acidamide;

6-(9-hydroxy-5,5dimethyl-nonyloxy)-2-methyl-hexane-2-sulfonic acidamide;

6-(9-hydroxy-5,5-dimethyl-nonyloxy)-2,2dimethyl-hexane-1-sulfonic acidamide;

7-(9-hydroxy-5,5-dimethyl-nonyloxy)-3,3-dimethyl-heptane-1-sulfonic acidamide;

8-(9-hydroxy-5,5-dimethyl-nonyloxy)-4,4-dimethyl-octane-1-sulfonic acidamide;

6-(10-hydroxy-5,5-dimethyl-decyloxy)-2-methyl-hexane-2-sulfonic acidamide;

6-(10-hydroxy-5,5-dimethyl-decyloxy)-2,2-dimethyl-hexane-1-sulfonic acidamide;

7-(10-hydroxy-5,5-dimethyl-decyloxy)-3,3-dimethyl-heptane-1-sulfonicacid amide;

8-(10-hydroxy-5,5-dimethyl-decyloxy)-4,4-dimethyl-octane-1-sulfonic acidamide;

9-(10-hydroxy-5,5-dimethyl-decyloxy)-5,5-dimethyl-nonane-1-sulfonic acidamide;

2,2-dimethyl-6-(5-methyl-5-sulfamoyl-hexyloxy)-hexanoic acid;

3,3-dimethyl-7-(5-methyl-5-sulfamoyl-hexyloxy)-heptanoic acid;

6-(5,5-dimethyl-6-sulfamoyl-hexyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-6-sulfamoyl-hexyloxy)-3,3-dimethyl-heptanoic acid;

6-(5,5-dimethyl-7-sulfamoyl-heptyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-7-sulfamoyl-heptyloxy)-3,3-dimethyl-heptanoic acid;

8-(5,5-dimethyl-7-sulfamoyl-heptyloxy)-4,4-dimethyl-octanoic acid;

6-(5,5-dimethyl-8-sulfamoyl-octyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-8-sulfamoyl-octyloxy)-3,3-dimethyl-heptanoic acid;

8-(5,5-dimethyl-8-sulfamoyl-octyloxy)-4,4-dimethyl-octanoic acid;

9-(5,5-dimethyl-8-sulfamoyl-octyloxy)-5,5-dimethyl-nonanoic acid;

6-(5,5-dimethyl-9-sulfamoyl-nonyloxy)-2,2-dimethyl-hexanoic acid;

7-(5,5-dimethyl-9-sulfamoyl-nonyloxy)-3,3-dimethyl-heptanoic acid;

8-(5,5-dimethyl-9-sulfamoyl-nonyloxy)-4,4-dimethyl-octanoic acid;

9-(5,5-dimethyl-9-sulfamoyl-nonyloxy)-5,5-dimethyl-nonanoic acid;

10-(5,5-dimethyl-9-sulfamoyl-nonyloxy)-6,6-dimethyl-decanoic acid;

2-methyl-6-(5-methyl-5-sulfamoyl-hexyloxy)-hexane-2-sulfonic acid amide;

2,2-dimethyl-6-(5-methyl-5-sulfamoyl-hexyloxy)-hexane-1-sulfonic acidamide;

6-(5,5-dimethyl-6-sulfamoyl-hexyloxy)-2,2-dimethyl-hexane-1-sulfonicacid amide;

3,3-dimethyl-7-(5-methyl-5-sulfamoyl-hexyloxy)-heptane-1-sulfonic acidamide;

7-(5,5-dimethyl-6-sulfamoyl-hexyloxy)-3,3-dimethyl-heptane-1-sulfonicacid amide;

7-(5,5-dimethyl-7-sulfamoyl-heptyloxy)-3,3-dimethyl-heptane-1-sulfonicacid amide;

4,4-dimethyl-8-(5-methyl-5-sulfamoyl-hexyloxy)-octace-1-sulfonic acidamide;

8-(5,5-dimethyl-6-sulfamoyl-hexyloxy)-4,4-dimethyl-octane-1-sulfonicacid amide;

8-(5,5-dimethyl-7-sulfamoyl-heptyloxy)-4,4-dimethyl-octane-1-sulfonicacid amide;

8-(5,5-dimethyl-8-sulfamoyl-octyloxy)-4,4-dimethyl-octane-1-sulfonicacid amide;

5,5-dimethyl-9-(5-methyl-5-sulfamoyl-hexyloxy)-nonane-1-sulfonic acidamide;

9-(5,5-dimethyl-6-sulfamoyl-hexyloxy)-5,5-dimethyl-nonane-1-sulfonicacid amide;

9-(5,5-dimethyl-7-sulfamoyl-heptyloxy)-5,5-dimethyl-nonane-1-sulfonicacid amide;

9-(5,5-dimethyl-9-sulfamoyl-octyloxy)-5,5-dimethyl-nonane-1-sulfonicacid amide;

9-(5,5-dimethyl-9-sulfamoyl-octyloxy)-5,5-dimethyl-nonane-1-sulfonicacid amide;

1-ethyl-3-[5-(6-hydroxy-5,5-dimethyl-hexyloxy)-1,1-dimethyl-pentyl]-imidazolidine-2,4-dione;

1-ethyl-3-[6-(6-hydroxy-5,5-dimethyl-hexyloxy)-2,2-dimethyl-hexyl]-imidazolidine-2,4-dione;

1-ethyl-3-[5-(7-hydroxy-5,5-dimethyl-heptyloxy)-1,1-dimethyl-pentyl]-imidazolidine-2,4-dione;

1-ethyl-3-[6-(7-hydroxy-5,5-dimethyl-heptyloxy)-2,2-dimethyl-hexyl]-imidazolidine-2,4-dione;

1-ethyl-3-[5-(8-hydroxy-5,5-dimethyl-octyloxy)-1,1-dimethyl-pentyl]-imidazolidine-2,4-dione;

1-ethyl-3-[6-(8-hydroxy-5,5-dimethyl-octyloxy)-2,2-dimethyl-hexyl]-imidazolidine-2,4-dione;

1-ethyl-3-[7-(8-hydroxy-5,5-dimethyl-octyloxy)-3,3-dimethyl-heptyl]-imidazolidine-2,4-dione;

1-ethyl-3-[5-(9-hydroxy-5,5-dimethyl-nonyloxy)-1,1-dimethyl-pentyl]-imidazolidine-2,4-dione;

1-ethyl-3-[6-(9-hydroxy-5,5-dimethyl-nonyloxy)-2,2-dimethyl-hexyl]-imidazolidine-2,4-dione;

1-ethyl-3-[7-(9-hydroxy-5,5-dimethyl-nonyloxy)-3,3-dimethyl-heptyl]-imidazolidine-2,4-dione;

1-ethyl-3-[8-(9-hydroxy-5,5-dimethyl-nonyloxy)-4,4-dimethyl-octyl]-imidazolidine-2,4-dione;

1-ethyl-3-[5-(10-hydroxy-5,5-dimethyl-decyloxy)-1,1-dimethyl-pentyl]-imidazolidine-2,4-dione;

1-ethyl-3-[6-(10-hydroxy-5,5-dimethyl-decyloxy)-2,2-dimethyl-hexyl]-imidazolidine-2,4-dione;

1-ethyl-3-[7-(10-hydroxy-5,5-dimethyl-decyloxy)-3,3-dimethyl-heptyl]-imidazolidine-2,4-dione;

1-ethyl-3-[8-(10-hydroxy-5,5-dimethyl-decyloxy)-4,4-dimethyl-octyl]-imidazolidine-2,4-dione;

1-ethyl-3-[9-(10-hydroxy-5,5-dimethyl-decyloxy)-5,5-dimethyl-nonyl]-imidazolidine-2,4-dione;

6-[5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5-methyl-hexyloxy]-2,2-dimethyl-hexanoicacid;

7-[5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5-methyl-hexyloxy]-3,3-dimethyl-heptanoicacid;

6-[6-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-hexyloxy]-2,2-dimethyl-hexanoicacid;

7-[6-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-hexyloxy]-3,3-dimethyl-heptanoicacid;

6-[7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-heptyloxy]-2,2-dimethyl-hexanoicacid;

7-[7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-heptyloxy]-3,3-dimethyl-heptanoicacid;

8-[7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-heptyloxy]-4,4-dimethyl-octanoicacid;

6-[8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy]-2,2-dimethyl-hexanoicacid;

7-[8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy]-3,3-dimethyl-heptanoicacid;

8-[8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy]-4,4-dimethyl-octanoicacid;

9-[8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy]-5,5-dimethyl-nonanoicacid;

6-[9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy)-2,2-dimethyl-hexanoicacid;

7-9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy]-3,3-dimethyl-heptanoicacid;

8-[9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy]-4,4-dimethyl-octanoicacid;

9-[9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy]-5,5-dimethyl-nonanoicacid;

10-[9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy]-6,6-dimethyl-decanoicacid;

3-[5-(5-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5-methyl-hexyloxy]-1,1-dimethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(6-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-hexyloxy]-1,1-dimethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(6-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-hexyloxy)-2,2-dimethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(7-cyclopentyl-5,5-dimethyl-heptyloxy)-1,1-dimethyl-pentyl]-1-ethyl-imadazolidine-2,4-dione;

3-[6-(7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-heptyloxy]-2,2-dimethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(7-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-heptyloxy]-3,3-dimethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy)-1,1-dimethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy]-2,2-dimethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy)-3,3-dimethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[8-(8-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-octyloxy)-4,4-dimethyl-octyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(9-cyclopentyl-5,5-dimethyl-nonyloxy)-1,1-dimethyl-pentyl]-1-ethyl-imidazolidine-2,4-dione;

3-[6-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy]-2,2-dimethyl-hexyl]-1-ethyl-imidazolidine-2,4-dione;

3-[7-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy]-3,3-dimethyl-heptyl]-1-ethyl-imidazolidine-2,4-dione;

3-[5-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy)-4,4-dimethyl-octyl]-1-ethyl-imidazolidine-2,4-dione;

3-[9-(9-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-5,5-dimethyl-nonyloxy)-5,5-dimethyl-nonyl]-1-ethyl-imidazolidine-2,4-dione;

LDH: Lactate dehdyrogenase

LDL: Low density lipoprotein

Lp(a): Lipoprotein (a)

MODY: Maturity onset diabetes of the young

NIDDM: Non-insulin dependent diabetes mellitus

PPAR: Peroxisome proliferator activated receptor

RXR: Retinoid X receptor

VLDL: Very low density lipoprotein

5.2. Compounds of the Invention

As used herein, the term “compounds of the invention” means,collectively, the compounds of formulas I, XL, XLI, and XLII andpharmaceutically acceptable salts thereof. The compounds of theinvention are identified herein by their chemical structure and/orchemical name. Where a compound is referred to by both a chemicalstructure and a chemical name, and that chemical structure and chemicalname conflict, the chemical structure is determinative of the compound'sidentity. The compounds of the invention may contain one or more chiralcenters and/or double bonds and, therefore, exist as stereoisomers, suchas double-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to the invention, the chemical structuresdepicted herein, and therefore the compounds of the invention, encompassall of the corresponding compound's enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric andstereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can beresolved into their component enantiomers or stereoisomers by well knownmethods, such as chiral-phase gas chromatography, chiral-phase highperformance liquid chromatography, crystallizing the compound as achiral salt complex, or crystallizing the compound in a chiral solvent.Enantiomers and stereoisomers can also be obtained from stereomerically-or enantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to an animal for veterinary use orfor improvement of livestock, or to a human for clinical use, thecompounds of the invention are administered in isolated form. As usedherein, “isolated” means that the compounds of the invention areseparated from other components of either (a) a natural source, such asa plant or cell, preferably bacterial culture, or (b) a syntheticorganic chemical reaction mixture. Preferably, via conventionaltechniques, the compounds of the invention are purified. As used herein,“purified” means that when isolated, the isolate contains at least 95%,preferably at least 98%, of a single ether compound of the invention byweight of the isolate.

The phrase “pharmaceutically acceptable salt(s),” as used hereinincludes but are not limited to salts of acidic or basic groups that maybe present in compounds used in the present compositions. Compoundsincluded in the present compositions that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. The acids that may be used to prepare pharmaceuticallyacceptable acid addition salts of such basic compounds are those thatform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, including but not limited tosulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide,hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, acid citrate,tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds, included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium lithium, zinc, potassium, andiron salts.

“Altering lipid metabolism” indicates an observable (measurable) changein at least one aspect of lipid metabolism, including but not limited tototal blood lipid content, blood HDL cholesterol, blood LDL cholesterol,blood VLDL cholesterol, blood triglyceride, blood Lp(a), blood apo A-1,blood apo E and blood non-esterified fatty acids.

“Altering glucose metabolism” indicates an observable (measurable)change in at least one aspect of glucose metabolism, including but notlimited to total blood glucose content, blood insulin, the blood insulinto blood glucose ratio, insulin sensitivity, and oxygen consumption.

A “therapeutically effective amount” of a composition of the inventionis measured by the therapeutic effectiveness of a compound of theinvention.

As used herein, the term “alkyl group” means a saturated, monovalentunbranched or branched hydrocarbon chain. Examples of alkyl groupsinclude, but are not limited to, (C₁-C₆)alkyl groups, such as methyl,ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,and hexyl, and longer alkyl groups, such as heptyl, and octyl. An alkylgroup can be unsubstituted or substituted with one or two suitablesubstituents.

An “alkenyl group” means a monovalent unbranched or branched hydrocarbonchain having one or more double bonds therein. The double bond of analkenyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkenyl groups include, but are not limited to(C₂-C₆)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

An “alkynyl group” means monovalent unbranched or branched hydrocarbonchain having one or more triple bonds therein. The triple bond of analkynyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkynyl groups include, but are not limited to,(C₂-C₆)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substitutedwith one or two suitable substituents.

An “aryl group” means a monocyclic or polycyclic-aromatic radicalcomprising carbon and hydrogen atoms. Examples of suitable aryl groupsinclude, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl,indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclicmoieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can beunsubstituted or substituted with one or two suitable substituents.Preferably, the aryl group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl”.

A “heteroaryl group” means a monocyclic- or polycyclic aromatic ringcomprising carbon atoms, hydrogen atoms, and one or more heteroatoms,preferably 1 to 3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. Illustrative examples of heteroaryl groups include,but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl,triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and(1,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, furyl, phienyl, isoxazolyl, and oxazolyl. Aheteroaryl group can be unsubstituted or substituted with one or twosuitable substituents. Preferably, a heteroaryl group is a monocyclicring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3heteroatoms, referred to herein as “(C₂-C₅)heteroaryl”.

A “cycloalkyl group” means a monocyclic or polycyclic saturated ringcomprising carbon and hydrogen atoms and having no carbon-carbonmultiple bonds. Examples of cycloalkyl groups include, but are notlimited to, (C₃-C₇)cycloalkyl groups, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic andbicyclic terpenes. A cycloalkyl group can be unsubstituted orsubstituted by one or two suitable substituents. Preferably, thecycloalkyl group is a monocyclic ring or bicyclic ring.

A “heterocycloalkyl group” means a monocyclic or polycyclic ringcomprising carbon and hydrogen atoms and at least one heteroatom,preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, andsulfur, and having no unsaturation. Examples of heterocycloalkyl groupsinclude pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl,piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,and pyranyl. A heterocycloalkyl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, theheterocycloalkyl group is a monocyclic or bicyclic ring, morepreferably, a monocyclic ring, wherein the ring comprises from 3 to 6carbon atoms and form 1 to 3 heteroatoms, referred to herein as(C₁-C₆)heterocycloalkyl.

As used herein a “heterocyclic radical” or “heterocyclic ring” means aheterocycloalkyl group or a heteroaryl group.

The term “alkoxy group” means an —O-alkyl group, wherein alkyl is asdefined above. An alkoxy group can be unsubstituted or substituted withone or two suitable substituents. Preferably, the alkyl chain of analkyloxy group is from 1 to 6 carbon atoms in length, referred to hereinas “(C₁-C₆)alkoxy”.

The term “aryloxy group” means an —O-aryl group, wherein aryl is asdefined above. An aryloxy group can be unsubstituted or substituted withone or two suitable substituents. Preferably, the aryl ring of anaryloxy group is a monocyclic ring, wherein the ring comprises 6 carbonatoms, referred to herein as “(C₆)aryloxy”.

The term “benzyl” means —CH₂-phenyl.

The term “phenyl” means —C₆H₅. A phenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

A “hydrocarbyl” group means a monovalent group selected from(C₁-C₈)alkyl, (C₂ C₈)alkenyl, and (C₂-C₈)alkynyl, optionally substitutedwith one or two suitable substituents. Preferably, the hydrocarbon chainof a hydrocarbyl group is from 1 to 6 carbon atoms in length, referredto herein as “(C₁-C₆)hydrocarbyl”.

A “carbonyl” group is a divalent group of the formula —C(O)—.

An “alkoxycarbonyl” group means a monovalent group of the formula—C(O)-alkoxy. Preferably, the hydrocarbon chain of an alkoxycarbonylgroup is from 1 to 8 carbon atoms in length, referred to herein as a“lower alkoxycarbonyl” group.

A “carbamoyl” group means the radical —C(O)N(R′)₂, wherein R′ is chosenfrom the group consisting of hydrogen, alkyl, and aryl.

As used herein, “halogen” means fluorine, chlorine, bromine, or iodine.Correspondingly, the meaning of the terms “halo” and “Hal” encompassfluoro, chloro, bromo, and iodo.

As used herein, a “suitable substituent” means a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: (C₁-C₈)alkyl;(C₁-C₈)alkenyl; (C₁-C₈)alkynyl; (C₆)aryl; (C₂-C₅)heteroaryl;(C₃-C₇)cycloalkyl; (C₁-C₈)alkoxy; (C₆)aryloxy; —CN; —OH; oxo; halo,—CO₂H; —NH₂; —NH((C₁-C₈)alkyl); —N((C₁-C₈)alkyl)₂; —NH((C₆)aryl);—N((C₆)aryl)₂; —CHO; —CO((C₁-C₈)alkyl); —CO((C₆)aryl);—CO₂((C₁-C₈)alkyl); and —CO₂((C₆)aryl). One of skill in art can readilychoose a suitable substituent based on the stability and pharmacologicaland synthetic activity of the compound of the invention.

5.3. Synthesis of the Compounds of the Invention

The compounds of the invention can be obtained via the syntheticmethodology illustrated in Schemes 1-9. Starting materials useful forpreparing the compounds of the invention and intermediates therefor, arecommercially available or can be prepared by well known syntheticmethods.

Scheme 1 illustrates the synthesis of mono-protected diols of theformula X, wherein n is an integer ranging from 0 to 5 and R¹ and R² areas defined above. Scheme 1 first outlines the synthesis ofmono-protected diols X, wherein n is 0, where esters of formula VII aresuccessively reacted with a first ((R¹)_(p)-M) then a second((R²)_(p)-M) organometallic reagent providing ketones of formula VIIIand alcohols of formula IX, respectively. M is a metal group and p isthe metal's valency value (e.g., the valency of Li is 1 and that of Znis 2). Suitable metals include, but are not limited to, Zn, Na, Li, and—Mg-Hal, wherein Hal is a halide selected from iodo, bromo, or chloro.Preferably, M is —Mg-Hal, in which case the organometallic reagents,(R¹)_(p)—Mg-Hal and (R²)_(p)—Mg-Hal, are known in the art as a Grignardreagents. Esters of formula VII are available commercially (e.g.,Aldrich Chemical Co., Milwaukee, Wis.) or can be prepared by well-knownsynthetic methods, for example, via esterification of the appropriate5-halovaleric acid (commercially available, e.g., Aldrich Chemical Co.,Milwaukee, Wis.). Both (R¹)_(p)-M and (R²)_(p)-M are availablecommercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or can beprepared by well-known methods (see e.g., Kharasch et al., GrignardReactions of Non-Metallic Substances; Prentice-Hall, Englewood Cliffs,N.J., pp. 138-528 (1954) and Hartley; Patai, The Chemistry of theMetal-Carbon Bond, Vol. 4, Wiley: New York, pp. 159-306 and pp. 162-175(1989), both citations are incorporated by reference herein). Thereaction of a first ((R¹)_(p)-M) then a second ((R²)_(p)-M)organometallic reagent with esters VII can be performed using thegeneral procedures referenced in March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 920-929 andEicher, Patai, The Chemistry of the Carbonyl Group, pt. 1, pp. 621-693;Wiley: New York, (1966), incorporated by reference herein. For example,the synthetic procedure described in Comins et al., 1981, TetrahedronLett. 22:1085, incorporated by reference herein, can be used. As oneexample, the reaction can be performed by adding an organic solution of(R¹)_(p)-M (about 0.5 to about 1 equivalents) to a stirred, cooled(about 0° C. to about −80° C.) solution comprising esters VII, under aninert atmosphere (e.g., nitrogen) to give a reaction mixture comprisingketones VIII. Preferably, (R¹)_(p)-M is added at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. The progress of the reactioncan be followed by using an appropriate analytical method, such asthin-layer chromatography or high-performance-liquid chromatography.Next, an organic solution of (R²)_(p)-M (about 0.5 to about 1equivalent) is added to the reaction mixture comprising ketones VIII inthe same manner used to add (R¹)_(p)-M. After the reaction providingalcohols IX is substantially complete, the reaction mixture can bequenched and the product can be isolated by workup. Suitable solventsfor obtaining alcohols IX include, but are not limited to,dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene,xylene, hydrocarbon solvents (e.g., pentane, hexane, and heptane), andmixtures thereof. Preferably, the organic solvent is diethyl ether ortetrahydrofuran. Next, alcohols IX are converted to mono-protected diolsX, wherein n is 0, using the well-known Williamson ether synthesis. Thisinvolves reacting alcohols IX with ⁻O-PG, wherein -PG is ahydroxy-protecting group. For a general discussion of the Williamsonether synthesis, see March, J. Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, pp. 386-387, and for a list ofprocedures and reagents useful in the Williamson ether synthesis seeLarock Comprehensive Organic Transformations; VCH: New York, 1989, pp.446-448, both of which references are incorporated herein by reference.As used herein, a “hydroxy-protecting group” means a group that isreversibly attached to a hydroxy moiety that renders the hydroxy moietyunreactive during a subsequent reaction(s) and that can be selectivelycleaved to regenerate the hydroxy moiety once its protecting purpose hasbeen served. Examples of hydroxy-protecting groups are found in Greene,T. W., Protective Groups in Organic Synthesis, 3rd edition 17-237(1999), incorporated herein by reference. Preferably, thehydroxy-protecting group is stable in a basic reaction medium, but canbe cleaved by acid. Examples of suitable base-stable acid-labilehydroxy-protecting groups suitable for use with the invention include,but are not limited to, ethers, such as methyl, methoxy methyl,methylthiomethyl, methoxyethoxymethyl, bis(2-chloroethoxy)methyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahyrofuranyl,tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl,allyl, benzyl, o-nitrobenzyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,1-butyldiphenylsilyl, tribenzylsilyl, and triisopropylsilyl; and esters,such as pivaloate, adamantoate, and 2,4,6-trimethylbenzoate. Ethers arepreferred, particularly straight chain ethers, such as methyl ether,methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether,bis(2-chloroethoxy)methyl ether. Preferably -PG is methoxymethyl(CH₃OCH₂—). Reaction of alcohols IX with ⁻O-PG under the conditions ofthe Williamson ether synthesis involves adding a base to a stirredorganic solution comprising HO-PG (e.g., methoxymethanol), maintained ata constant temperature within the range of about 0° C. to about 80° C.,preferably at about room temperature. Preferably, the base is added at arate such that the reaction-mixture temperature remains within about oneto two degrees of the initial reaction-mixture temperature. The base canbe added as an organic solution or in undiluted form. Preferably, thebase will have a base strength sufficient to deprotonate a proton,wherein the proton has a pK_(a) of greater than about 15, preferablygreater than about 20. As is well known in the art, the pK_(a) is ameasure of the acidity of an acid H-A, according to the equationpK_(a)=−log K_(a), wherein K_(a) is the equilibrium constant for theproton transfer. The acidity of an acid H-A is proportional to thestability of its conjugate base ⁻A. For tables listing pK_(a) values forvarious organic acids and a discussion on pK_(a) measurement, see March,J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, pp. 248-272, incorporated herein by reference. Suitable basesinclude, but are not limited to, alkylmetal bases such as methyllithium,n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium,phenyl sodium, and phenyl potassium; metal amide bases such as lithiumamide, sodium amide, potassium amide, lithium tetramethylpiperidide,lithium diisopropylamide, lithium diethylamide, lithiumdicyclohexylamide, sodium hexamethyldisilazide, and lithiumhexamethyldisilazide; and hydride bases such as sodium hydride andpotassium hydride. The preferred base is lithium diisopropylamide.Solvents suitable for reacting alcohols IX with -OPG include, but arenot limited, to dimethyl sulfoxide, dichloromethane, ethers, andmixtures thereof, preferably tetrahydrofuran. After addition of thebase, the reaction mixture can be adjusted to within a temperature rangeof about 0° C. to about room temperature and alcohols IX can be added,preferably at a rate such that the reaction-mixture temperature remainswithin about one to two degrees of the initial reaction-mixturetemperature. Alcohols of formula IX can be diluted in an organic solventor added in their undiluted form. The resulting reaction mixture isstirred until the reaction is substantially complete as determined byusing an appropriate analytical method, preferably by gaschromatography, then the mono-protected diols X can be isolated byworkup and purification.

Next, Scheme 1 outlines a method useful for synthesizing mono-protecteddiols X, wherein n is 1. First, compounds of formula XI, wherein X is asuitable leaving group, are reacted with compounds of formula XII,wherein R¹ and R² are as defined above and R⁸ is H, (C₁-C₆)alkyl or(C₆)aryl, providing compounds of formula XIII. Compounds of formula XIare available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.)or can be prepared by well-known methods such as halogenation orsulfonation of butanediol. Compounds of formula XII are also availablecommercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or bywell-known methods, such as those listed in Larock Comprehensive OrganicTransformations; Wiley-VCH: New York, 1999, pp. 1754-1755 and 1765. Areview on alkylation of esters of type XII is given in J. Mulzer inComprehensive Organic Functional Transformations, Pergamon, Oxford 1995,pp. 148-151 and exemplary synthetic procedures for reacting compounds offormula XI with compounds of formula XII are described in U.S. Pat. No.5,648,387, column 6 and Ackerly, et al., 1995, J. Med. Chem. 1608, allof which citations are incorporated by reference herein. The reactionrequires the presence of a suitable base. Preferably, a suitable basewill have a pK_(a) of greater than about 25, more preferably greaterthan about 30. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, see-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; hydridebases such as sodium hydride and potassium hydride. Metal amide bases,such as lithium diisopropylamide are preferred. Preferably, to reactcompounds of formula XI with compounds of formula XII, a solution ofabout 1 to about 2 equivalents of a suitable base is added to a stirredsolution comprising esters of formula XII and a suitable organicsolvent, under an inert atmosphere, the solution maintained at aconstant temperature within the range of about −95° C. to about roomtemperature, preferably at about −78° C. to about −20° C. Preferably,the base is diluted in a suitable organic solvent before addition.Preferably, the base is added at a rate of about 1.5 moles per hour.Organic solvents suitable for the reaction of compounds of formula XIwith the compounds of formula XII include, but are not limited to,dichloromethane, diethyl ether, tetrahydrofuran, dimethylformamide,dimethyl sulfoxide, benzene, toluene, xylene, hydrocarbon solvents (e g,pentane, hexane, and heptane), and mixtures thereof. After addition ofthe base, the reaction mixture is allowed to stir for about 1 to about 2hours, and a compound of formula XI, preferably dissolved in a suitableorganic solvent, is added, preferably at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. After addition of compounds offormula XI, the reaction-mixture temperature can be adjusted to within atemperature range of about −20° C. to about room temperature, preferablyto about room temperature, and the reaction mixture is allowed to stiruntil the reaction is substantially complete as determined by using anappropriated analytical method, preferably thin-layer chromatography orhigh-performance liquid chromatography. Then the reaction mixture isquenched and compounds XIII, wherein n is 1 can be isolated by workup.Compounds XIV are then synthesized by reacting compounds XIII with ⁻O-PGaccording to the protocol described above for reacting alcohols IX with⁻O-PG. Next, compounds XIV can be converted to mono-protected diols X,wherein n is 1, by reduction of the ester group of compounds XIV to analcohol group with a suitable reducing agent. A wide variety of reagentsare available for reduction of such esters to alcohols, e.g., see M.Hudlicky, Reductions in Organic Chemistry, 2nd ed., 1996 pp. 212-217,incorporated by reference herein. Preferably, the reduction is effectedwith a hydride type reducing agent, for example, lithium aluminumhydride, lithium borohydride, lithium triethyl borohydride,diisobutylaluminum hydride, lithium trimethoxyaluminum hydride, orsodium bis(2-methoxy)aluminum hydride. For exemplary procedures forreducing esters to alcohols, see Nystrom et al, 1947, J. Am. Chem. Soc.69:1197; and Moffet et al., 1963, Org. Synth., Collect. 834(4), lithiumaluminum hydride; Brown et al., 1965, J. Am. Chem. Soc. 87:5614, lithiumtrimethoxyaluminum hydride; Cerny et al., 1969, Collect. Czech. Chem.Commun. 34:1025, sodium bis(2-methoxy)aluminum hydride; Nystrom et al.,1949, J. Am. Chem. 71:245, lithium borohydride; and Brown et al., 1980,J. Org. Chem. 45:1, lithium triethyl borohydride, all of which citationsare incorporated herein by reference. Preferably, the reduction isconducted by adding an organic solution of compounds XIV to a stirredmixture comprising a reducing agent, preferably lithium aluminumhydride, and an organic solvent. During the addition, the reactionmixture is maintained at a constant temperature 3 within the range ofabout −20° C. to about 80° C., preferably at about room temperature.Organic solvents suitable for reacting XIII with -OPG include, but arenot limited to, dichloromethane, diethyl ether, tetrahydrofuran ormixtures thereof, preferably tetrahydrofuran. After the addition, thereaction mixture is stirred at a constant temperature within the rangeof about room temperature to about 60° C., until the reaction issubstantially 3 complete as determined by using an appropriateanalytical method, preferably thin-layer chromatography orhigh-performance-liquid chromatography. Then the reaction mixture can bequenched and mono-protected diols X, wherein n is 1, can be isolated byworkup and purification.

Scheme 1 next illustrates a three step synthetic sequence forhomologating mono-protected diols X comprising: (a) halogenation(converting —CH₂OH to —CH₂-Hal); (b) carbonylation (replacing -Hal with—CHO); and (c) reduction (converting —CHO to —CH₂OH), wherein a reactionsequence of (a), (b), and (c) increases the value of n by 1. In step (a)protected halo-alcohols of formula XV, wherein Hal is a halide selectedfrom the group of chloro, bromo, or iodo, preferably iodo, can beprepared by halogenating mono-protected diols X, by using well-knownmethods (for a discussion of various methods for conversion of alcoholsto halides see March, J. Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, pp. 431-433, incorporatedherein by reference). For example, protected iodo-alcohols XV can besynthesized starting from mono-protected diols X by treatment withPh₃/I₂/imidazole (Garegg et al., 1980, J.C.S Perkin I 2866);1,2-dipheneylene phosphorochloridite/I₂ (Corey et al., 1967, J. Org.Chem. 82:4160); or preferably with Me₃SiCl/NaI (Olah et al., 1979, J.Org. Chem. 44:8, 1247), all of which citations are incorporated byreference herein. Step (b); carbonylation of alkyl halides, such asprotected halo-alcohols XV, is reviewed in Olah et al., 1987, Chem Rev.87:4, 671; and March, J., Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, pp. 483-484, both of which areincorporated by reference herein). Protected halo-alcohols XV can becarbonylated with Li(BF₃.Et₂O)/HCONMe₂ using the procedure described inMaddaford et al., 1993, J. Org. Chem. 58:4132; Becker et al., 1982, J.Org. Chem. 3297; or Myers et al., 1992, J. Am. Chem. Soc. 114:9369 or,alternatively, with an organometallic/N-formylmorpholine using theprocedure described in Olah et al., 1984, J. Org. Chem. 49:3856 orVogtle et al., 1987, J. Org. Chem. 52:5560, all of which citations areincorporated by reference herein. The method of described in Olah etal., 1984, J. Org. Chem. 49:3856 is preferred. Reduction step (c) usefulfor synthesizing mono-protected diols X from aldehydes of formula XVI,can be accomplished by well-known methods in the art for reduction ofaldehydes to the corresponding alcohols (for a discussion see M.Hudlicky, Reductions in Organic Chemistry, 2nd ed., 1996 pp 137-139),for example, by catalytic hydrogenation (see e.g, Carothers, 1949, J AmChem Soc. 46:1675) or, preferably by reacting aldehydes XVI with ahydride reducing agent, such as lithium aluminum hydride, lithiumborohydride, sodium borohydride (see e.g., the procedures described inChaikin et al., 1949, J. Am Chem. Soc. 71:3245; Nystrom et al., 1947, J.Am. Chem. Soc. 69:1197; and Nystrom et al., 1949, J. Am. Chem. 71:3245,all of which are incorporated by reference herein). Reduction withlithium aluminum hydride is preferred.

Scheme 2 outlines methodology for the synthesis of protected alcohols offormula XVII, wherein K¹, R¹, R², and n are defined as above, whichprotected alcohols can be converted to alcohols of formula XVIII byhydroxy-group deprotection. Protected alcohols XVII, wherein K¹ is—C(O)OH, can be synthesized by oxidizing mono-protected diols X with anagent suitable for oxidizing a primary alcohol to a carboxylic acid (fora discussion see M. Hudlicky, Oxidations in Organic Chemistry, ACSMonograph 186, 1990, pp. 127-130, incorporated by reference herein).Suitable oxidizing agents include, but are not limited to, pyridiniumdichromate (Corey et al., 1979, Tetrahedron Lett. 399); manganesedioxide (Ahrens et al., 1967, J. Heterocycl. Chem. 4:625); sodiumpermanganate monohydrate (Menger et al., 1981, Tetrahedron Lett.22:1655); and potassium permanganate (Sam et al., 1972, J. Am. Chem.Soc. 94:4024), all of which citations are incorporated by referenceherein. The preferred oxidizing reagent is pyridinium dichromate. In analternative synthetic procedure, protected alcohols XVII, wherein K¹ is—C(O)OH, can be synthesized by treatment of protected halo-alcohols XV,wherein X is iodo, with CO or CO₂, as described in Bailey et al., 1990,J. Org. Chem. 55:5404 and Yanagisawa et al., 1994, J. Am. Chem. Soc.116:6130, the two of which citations are incorporated by referenceherein. Protected alcohols XVII, wherein K¹ is —C(O)OR⁵, wherein R⁵ isas defined above, can be synthesized by oxidation of mono-protecteddiols X in the presence of R⁵OH (see generally, March, J. AdvancedOrganic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992,p. 1196). An exemplary procedures for such an oxidation are described inStevens et al., 1982, Tetrahedron Lett. 23:4647 (HOCl); Sundararaman etal., 1978, Tetrahedron Lett. 1627 (O₃/KOH); Wilson et al., 1982, J. Org.Chem. 47:1360 (t-BuOOH/Et₃N); and Williams et al., 1988, TetrahedronLett. 29:5087 (Br₂), the four of which citations are incorporated byreference herein. Preferably, protected alcohols XVII, wherein K¹ is—C(O)OR⁵ are synthesized from the corresponding carboxylic acid (i.e.,XVII, wherein K¹ is —C(O)OH) by esterification with R⁵OH (erg., seeMarch, J., Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, p. 393-394, incorporated by reference herein).In another alternative synthesis, protected alcohols XVII, wherein K¹ is—C(O)OR⁵, can be prepared from protected halo-alcohols XV bycarbonylation with transition metal complexes (see e.g., March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 484-486; Urata et al., 1991, Tetrahedron Lett. 32:36,4733); and Ogata et al., 1969, J. Org. Chem. 3985, the three of whichcitations are incorporated by reference herein).

Protected alcohols XVII, wherein K¹ is OC(O)R⁵, wherein R⁵ is as definedabove, can be prepared by acylation of mono-protected diols X with acarboxylate equivalent such as an acyl halide (i.e., R⁵C(O)-Hal, whereinHal is iodo, bromo, or chloro, see e.g., March, J. Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. 392and Org. Synth. Coil. Vol. III, Wiley, NY, pp. 142, 144, 167, and 187(1955)) or an anhydride (i.e., R⁵C(O)—O—(O)CR⁵, see e.g., March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 392-393 and Org. Synth. Coll. Vol. III, Wiley, NY, pp. 11,127, 141, 169, 237, 281, 428, 432, 690, and 833 (1955), all of whichcitations are incorporated herein by reference). Preferably, thereaction is conducted by adding a base to a solution comprisingmono-protected diols X, a carboxylate equivalent, and an organicsolvent, which solution is preferably maintained at a constanttemperature within the range of 0° C. to about room temperature.Solvents suitable for reacting mono-protected diols X with a carboxylateequivalent include, but are not limited to, dichloromethane, toluene,and ether, preferably dichloromethane. Suitable bases include, but arenot limited to, hydroxide sources, such as sodium hydroxide, potassiumhydroxide, sodium carbonate, or potassium carbonate; or an amine such astriethylamine, pyridine, or dimethylaminopyridine, amines are preferred.The progress of the reaction can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography and when substantially complete, theproduct can be isolated by workup and purified if desired.

Protected alcohols XVII, wherein K¹ is one of the following phosphateester groups

wherein R⁶ is defined as above, can be prepared by phosphorylation ofmono-protected diols X according to well-known methods (for a generalreviews, see Corbridge Phosphorus: An Outline of its Chemistry,Biochemistry, and Uses, Studies in Inorganic Chemistry, 3rd ed., pp.357-395 (1985); Ramirez et al, 1978, Acc. Chem. Res. 11:239; andKalckare Biological Phosphorylations, Prentice-Hall, New York (1969); J.B. Sweeny in Comprehensive Organic Functional Group Transformations, A.R. Katritzky, O. Meth-Collhn and C. W. Rees, Eds. Pergamon: Oxford,1995, vol 2, pp. 104-109, the four of which are incorporated herein byreference). Protected alcohols XVII wherein K¹ is a monophosphate groupof the formula:

wherein R⁶ is defined as above, can be prepared by treatment ofmono-protected diol X with phosphorous oxychloride in a suitablesolvent, such as xylene or toluene, at a constant temperature within therange of about 100° C. to about 150° C. for about 2 hours to about 24hours. After the reaction is deemed substantially complete, by using anappropriate analytical method, the reaction mixture is hydrolyzed withR⁶—OH. Suitable procedures are referenced in Houben-Weyl, Methoden derOrganische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2, pp.143-210 and 872-879, incorporated by reference herein. Alternatively,when both R⁶ are hydrogen, can be synthesized by reacting mono-protecteddiols X with silyl polyphosphate (Okamoto et al., 1985, Bull Chem. Soc.Jpn. 58:3393, incorporated herein by reference) or by hydrogenolysis oftheir benzyl or phenyl esters (Chen et al., 1998, J. Org. Chem. 63:6511,incorporated herein by reference). In another alternative procedure,when R⁶ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl, themonophosphate esters can be prepared by reacting mono-protected diols Xwith appropriately substituted phophoramidites followed by oxidation ofthe intermediate with m-chloroperbenzoic acid (Yu et al., 1988,Tetrahedron Lett. 29:979, incorporated herein by reference) or byreacting mono-protected diols X with dialkyl or diaryl substitutedphosphorochloridates (Pop, et al, 1997, Org. Prep. and Proc. Int.29:341, incorporated herein by reference). The phosphoramidites arecommercially available (e.g., Aldrich Chemical Co., Milwaukee, Wis.) orreadily prepared according to literature procedures (see e.g, Uhlmann etal. 1986, Tetrahedron Lett. 27:1023 and Tanaka et al., 1988, TetrahedronLett. 29:199, both of which are incorporated herein by reference). Thephosphorochloridates are also commercially available (e.g., AldrichChemical Co., Milwaukee, Wis.) or prepared according to literaturemethods (e.g., Gajda et al, 1995, Synthesis 25:4099. In still anotheralternative synthesis, protected alcohols XVII, wherein K¹ is amonophosphate group and R⁶ is alkyl or aryl, can be prepared by reactingIP⁴(OR⁶)₃ with mono-protected diols X according to the proceduredescribed in Stowell et al., 1995, Tetrahedron Lett. 36:11, 1825 or byalkylation of protected halo alcohols XV with the appropriate dialkyl ordiaryl phosphates (see e.g., Okamoto, 1985, Bull Chem. Soc. Jpn.58:3393, incorporated herein by reference).

Protected alcohols XVII wherein K¹ is a diphosphate group of the formula

wherein R⁶ is defined as above, can be synthesized by reacting protectedalcohols XVII, of the formula:

with a phosphate of the formula:

(commercially available, e.g., Aldrich Chemical Co., Milwaukee, Wis.),in the presence of carbodiimide such as dicyclohexylcarbodiimide, asdescribed in Houben-Weyl, Methoden der Organische Chemie, Georg ThiemeVerlag Stuttgart 1964, vol. XII/2, pp. 881-885. In the same fashion,protected alcohols XVII, wherein K¹ is a triphosphate group of theformula:

can be synthesized by reacting diphosphate protected alcohols XVII, ofthe formula:

with the compound of the formula:

as described above. Alternatively, when R⁶ is H, protected alcohols XVIIwherein K¹ is the triphosphate group, can be prepared by reactingmono-protected diols X with salicyl phosphorochloridite and thenpyrophosphate and subsequent cleavage of the adduct thus obtained withiodine in pyridine as described in Ludwig et al., 1989, J. Org. Chem.54:631, incorporated herein by reference.

Protected alcohols XVII, wherein K¹ is —SO₃H or a heterocyclic groupselected from the group consisting of:

can be prepared by halide displacement from protected halo-alcohols XV.Thus, when K¹ is —SO₃H, protected alcohols XVII can by synthesized byreacting protected halo-alcohols XV with sodium sulfite as described inGilbert Sulfonation and Related Reactions; Wiley: New York, 1965, pp.136-148 and pp. 161-163; Org. Synth. Coll. Vol. II, Wiley, NY, 558, 564(1943); and Org. Synth. Coll. Vol. IV, Wiley, NY, 529 (1963), all threeof which are incorporated herein by reference. When K¹ is one of theabove-mentioned heterocycles, protected alcohols XVII can be prepared byreacting protected halo-alcohols XV with the corresponding heterocyclein the presence of a base. The heterocycles are available commercially(e.g., Aldrich Chemical Co., Milwaukee, Wis.) or prepared by well-knownsynthetic methods (see the procedures described in Ware, 1950, Chem.Rev. 46:403-470, incorporated herein by reference). Preferably, thereaction is conducted by stirring a mixture comprising XV, theheterocycle, and a solvent at a constant temperature within the range ofabout room temperature to about 100° C., preferably within the range ofabout 50° C. to about 70° C. for about 10 to about 48 hours. Suitablebases include hydroxide bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate, or potassium carbonate. Preferably, thesolvent used in forming protected alcohols XVII is selected fromdimethylformamide; formamide; dimethyl sulfoxide; alcohols, such asmethanol or ethanol; and mixtures thereof. The progress of the reactioncan be followed by using an appropriate analytical technique, such asthin layer chromatography or high performance liquid chromatography andwhen substantially complete, the product can be isolated by workup andpurified if desired.

Protected alcohols XVII, wherein K¹ is a heteroaryl ring selected from

can be prepared by metallating the suitable heteroaryl ring thenreacting the resulting metallated heteroaryl ring with protectedhalo-alcohols XV (for a review, see Katritzky Handbook of HeterocyclicChemistry, Pergamon Press: Oxford 1985). The heteroaryl rings areavailable commercially or prepared by well-known synthetic methods (seee.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995; De Sarlo etal., 1971, J. Chem. Soc. (C) 86; Oster et al., 1983, J. Org. Chem.48:4307; Iwai et al., 1966, Chem. Pharm. Bull. 14:1277; and U.S. Pat.No. 3,152,148, all of which citations are incorporated herein byreference). As used herein, the term “metallating” means the forming ofa carbon-metal bond, which bond may be substantially ionic in character.Metallation can be accomplished by adding about 2 equivalents of strongorganometallic base, preferably with a pK_(a) of about 25 or more, morepreferably with a pK_(a) of greater than about 35, to a mixturecomprising a suitable organic solvent and the heterocycle. Twoequivalents of base are required: one equivalent of the basedeprotonates the —OH group or the —NH group, and the second equivalentmetallates the heteroaryl ring. Alternatively, the hydroxy group of theheteroaryl ring can be protected with a base-stable, acid-labileprotecting group as described in Greene, T. W., Protective Groups inOrganic Synthesis, 3rd edition 17-237 (1999), incorporated herein byreference. Where the hydroxy group is protected, only one equivalent ofbase is required. Examples of suitable base-stable, acid-labilehydroxyl-protecting groups, include but are not limited to, ethers, suchas methyl, methoxy methyl, methylthiomethyl, methoxyethoxymethyl,bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahyrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl,1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, o-nitrobenzyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl; and esters,such as pivaloate, adamantoate, and 2,4,6-trimethylbenzoate. Ethers arepreferred, particularly straight chain ethers, such as methyl ether,methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether,bis(2-chloroethoxy)methyl ether. Preferably, the pK_(a) of the base ishigher than the pK_(a) of the proton of the heterocycle to bedeprotonated. For a listing of pK_(a)s for various heteroaryl rings, seeFraser et al., 1985, Can. J. Chem. 63:3505, incorporated herein byreference. Suitable bases include, but are not limited to, alkylmetalbases such as methyllithium, n-butyllithium, tert-butyllithium,sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium;metal amide bases such as lithium amide, sodium amide, potassium amide,lithium tetramethylpiperidide, lithium diisopropylamide, lithiumdiethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide,and lithium hexamethyldisilazide; and hydride bases such as sodiumhydride and potassium hydride. If desired, the organometallic base canbe activated with a complexing agent, such asN,N,N′,N′-tetramethylethylenediamine or hexamethylphosphoramide (1970,J. Am. Chem. Soc. 92:4664, incorporated by reference herein). Solventssuitable for synthesizing protected alcohols XVII, wherein K¹ is aheteroaryl ring include, but are not limited to, diethyl ether;tetrahydrofuran; and hydrocarbons, such as pentane. Generally,metallation occurs alpha to the heteroatom due to the inductive effectof the heteroatom, however, modification of conditions, such as theidentity of the base and solvents, order of reagent addition, reagentaddition times, and reaction and addition temperatures can be modifiedby one of skill in the art to achieve the desired metallation position(see e g, Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, pp.30-42, incorporated by reference herein) Alternatively, the position ofmetallation can be controlled by use of a halogenated heteroaryl group,wherein the halogen is located on the position of the heteroaryl ringwhere metallation is desired (see e.g., Joule et al., HeterocyclicChemistry, 3rd ed., 1995, p. 33 and Saulnier et al., 1982, J. Org. Chem.47:757, the two of which citations are incorporated by referenceherein). Halogenated heteroaryl groups are available commercially (e.g.,Aldrich Chemical Co., Milwaukee, Wis.) or can be prepared by well-knownsynthetic methods (see e.g., Joule et al., Heterocyclic Chemistry, 3rded., 1995, pp. 78, 85, 122, 193, 234, 261, 280, 308, incorporated byreference herein). After metallation, the reaction mixture comprisingthe metallated heteroaryl ring is adjusted to within a temperature rangeof about 0° C. to about room temperature and protected halo-alcohols XV(diluted with a solvent or in undiluted form) are added, preferably at arate such that the reaction-mixture temperature remains within about oneto two degrees of the initial reaction-mixture temperature. Afteraddition of protected halo-alcohols XV, the reaction mixture is stirredat a constant temperature within the range of about room temperature andabout the solvent's boiling temperature and the reaction's progress canbe monitored by the appropriate analytical technique, preferablythin-layer chromatography or high-performance liquid chromatography.After the reaction is substantially complete, protected alcohols XVIIcan be isolated by workup and purification. It is to be understood thatconditions, such as the identity of protected halo-alcohol XV, the base,solvents, orders of reagent addition, times, and temperatures, can bemodified by one of skill in the art to optimize the yield andselectivity. Exemplary procedures that can be used in such atransformation are described in Shirley et al., 1995, J. Org. Chem.20:225; Chadwick et al., 1979, J. Chem. Soc., Perkin Trans. 1 2845;Rewcastle, 1993, Adv. Het. Chem. 56:208; Katritzky et al., 1993, Adv.Het. Chem. 56:155; and Kessar et al., 1997, Chem. Rev. 97:721.

Protected alcohols XVII, wherein K¹ is a lactone selected from:

can be prepared from compounds of the formula X, XV, or XVI by usingwell-known condensation reactions and variations of the Michaelreaction. Methods for the synthesis of lactones are disclosed in Multzerin Comprehensive Organic Functional Group Transformations, A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Eds. Pergamon: Oxford, 1995, vol5, pp. 161-173, incorporated herein by reference. When K¹ is abeta-lactone of the formula:

protected alcohols XVII can be prepared from aldehydes XVI and protectedhalo-alcohols XV, respectively, by a one-pot-addition-lactonizationaccording to the procedure of Masamune et al., 1976, J. Am. Chem. Soc.98:7874 and Danheiser et al., 1991, J. Org. Chem. 56:1176, both of whichare incorporated herein by reference. Thisone-pot-addition-lactonization methodology has been reviewed by Multzerin Comprehensive Organic Functional Group Transformations, A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Eds. Pergamon: Oxford, 1995, vol5, pp. 161, incorporated herein by reference When K¹ is a gamma- ordelta-lactone of the formula:

protected alcohols XVII can be prepared from aldehydes XVI according towell known synthetic methodology. For example, the methodology describedin Masuyama et al., 2000, J. Org. Chem. 65:494; Eisch et al., 1978, JOrgano. Met. Chem. C8 160; Eaton et al., 1947, J. Org. Chem.37:1947;Yunker et al., 1978, Tetrahedron Lett. 4651; Bhanot et al, 1977,J. Org. Chem. 42:1623; Ehlinger et al., 1980, J. Am. Chem. Soc.102:5004; and Raunio et al., 1957, J. Org. Chem 22:570, all of whichcitations are incorporated herein by reference. For instance, asdescribed in Masuyama et al., 2000, J. Org. Chem. 65:494, aldehydes XVIcan be treated with about 1 equivalent of a strong organometallic base,preferably with a pK_(a) of about 25 or more, more preferably with apK_(a) of greater than about 35, in a suitable organic solvent to give areaction mixture. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Suitable solvents include, but are notlimited to, diethyl ether and tetrahydrofuran. The reaction-mixturetemperature is adjusted to within the range of about 0° C. to about 100°C., preferably about room temperature to about 50° C., and a halide ofthe formula:

wherein z is 1 or 2 (diluted with a solvent or in undiluted form) isadded. The reaction mixture is stirred for a period of about 2 hours toabout 48 hours, preferably about 5 to about 10 hours, during which timethe reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, protected alcohols XVII can be isolated byworkup and purified if desired. When K¹ is a gamma- or delta-lactone ofthe formula:

protected alcohols XVII can be synthesized by deprotonating therespective lactone with a strong base providing the correspondinglactone enolate and reacting the enolate with protected halo-alcohols XV(for a detailed discussion of enolate formation of active methylenecompounds such as lactones, see House Modern Synthetic Reactions; W. A.Benjamin, Inc. Philippines 1972 pp. 492-570, and for a discussion ofreaction of lactone enolates with electrophiles such as carbonylcompounds, see March, J. Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, pp. 944-945, both of which areincorporated herein by reference). Lactone-enolate formation can beaccomplished by adding about 1 equivalent of a strong organometallicbase, preferably with a pK_(a) of about 25 or more, more preferably witha pK_(a) of greater than about 35, to a mixture comprising a suitableorganic solvent and the lactone. Suitable bases include, but are notlimited to, alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Solvents suitable for lactone-enolateformation include, but are not limited to, diethyl ether andtetrahydrofuran. After enolate formation, the reaction-mixturetemperature is adjusted to within the range of about −78° C. to aboutroom temperature, preferably about −50° C. to about 0° C., and protectedhalo-alcohols XV (diluted with a solvent or in undiluted form) areadded, preferably at a rate such that the reaction-mixture temperatureremains within about one to two degrees of the initial reaction-mixturetemperature. The reaction mixture is stirred for a period of about 15minutes to about 5 hours, during which time the reaction's progress canbe followed by using an appropriate analytical technique, such as thinlayer chromatography or high performance liquid chromatography. When thereaction is deemed substantially complete, protected alcohols XVII canbe isolated by workup and purified if desired. Protected alcohols XVII,wherein K¹ is a lactone of the formula:

can be prepared from aldehydes XVI according to the procedure describedin U.S. Pat. No. 4,622,338, incorporated by reference herein.

When K¹ is a gamma- or delta-lactone of the formula:

protected alcohols XVII can bc prepared according to a three stepsequence. The first step comprises base-mediated reaction of protectedhalo-alcohols XV with succinic acid esters (i.e., RO₂CCH₂CH₂CO₂R,wherein R is alkyl) or glutaric acid esters (i.e., RO₂CCH₂CH₂CH₂CO₂R,wherein R is alkyl) providing a diester intermediate of the formula:

wherein z is 1 or 2 depending on the acid ester starting material. Thereaction can be performed by adding about 1 equivalent of a strongorganometallic base, preferably with a pK_(a) of about 25 or more, morepreferably with a pK_(a) of greater than about 35, to a mixturecomprising a suitable organic solvent and the succinic or glutaric acidester. Suitable bases include, but are not limited to, alkylmetal basessuch as methyllithium, n-butyllithium, tert-butyllithium,sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium;metal amide bases such as lithium amide, sodium amide, potassium amide,lithium tetramethylpiperidide, lithium diisopropylamide, lithiumdiethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide,and lithium hexamethyldisilazide; and hydride bases such as sodiumhydride and potassium hydride, preferably lithium tetramethylpiperidide.Suitable solvents include, but are not limited to, diethyl ether andtetrahydrofuran. After enolate formation, the reaction-mixturetemperature is adjusted to within the range of about −78° C. to aboutroom temperature, preferably about −50° C. to about 0° C., and protectedhalo-alcohols XV (diluted with a solvent or in undiluted form) areadded, preferably at a rate such that the reaction-mixture temperatureremains within about one to two degrees of the initial reaction-mixturetemperature. The reaction mixture is stirred for a period of about 15minutes to about 5 hours, during which time the reaction's progress canbe followed by using an appropriate analytical technique, such as thinlayer chromatography or high performance liquid chromatography. When thereaction is deemed substantially complete, the diester intermediate beisolated by workup and purified if desired. In the second step, theintermediate diester can be reduced, with a hydride reducing agent, toyield a diol of the formula:

The reduction can be performed according to the procedures referenced inMarch, J. Advance Organic Chemistry, Reactions Mechanisms, andStructure, 4th ed., 1992, p. 1214, incorporated herein by reference).Suitable reducing agents include, but are not limited to, lithiumaluminum hydride, diisobutylaluminum hydride, sodium borohydride, andlithium borohydride). In the third step, the diol can be oxidativelycyclized with RuH₂(PPh₃)₄ to the product lactones XVII according to theprocedure of Yoshikawa et al., 1986, J. Org. Chem. 51:2034 and Yoshikawaet al., 1983, Tetrahedron Lett. 26:2677, both of which citations areincorporated herein by reference. When K¹ is a lactone of the formula:

protected alcohols XVII can be synthesized by reacting the Grignardsalts of protected halo-alcohols XV with 5,6-dihydro-2H-pyran-2-one,commercially available (e.g., Aldrich Chemical Co., Milwaukee, Wis.), inthe presence of catalytic amounts of a1-dimethylaminoacetyl)pyrolidine-2yl)methyl-diarylphosphine-copper (I)iodide complex as described in Tomioka et al., 1995, Tetrahedron Lett.36:4275, incorporated herein by reference. When K¹ is

protected alcohols XVII can be prepared from their correspondingcarboxylic acid derivatives (XVII, wherein K¹ is —CO₂H) as described inBelletire et al, 1988, Synthetic Commun. 18:2063 or from thecorresponding acylchlorides (XVII, wherein K¹ is —CO-halo) as describedin Skinner et al., 1995, J. Am. Chem. Soc. 77:5440, both citations areincorporated herein by reference. The acylhalides can be prepared fromthe carboxylic acids by well known procedures such as those described inMarch, J., Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, pp. 437-438, incorporated by reference herein.When K¹ is

wherein R⁷ is as defined above, protected alcohols XVII can be preparedby first reacting protected halo-alcohols XV with a trialkyl phosphiteaccording to the procedure described in Kosolapoff, 1951, Org. React.6:273 followed by reacting the derived phosphonic diester with ammoniaaccording to the procedure described in Smith et al., 1957, J. Org.Chem. 22:265, incorporated herein by reference. When K¹ is

protected alcohols XVII can be prepared by reacting their sulphonic acidderivatives (i.e., XVII, wherein K¹ is —SO₃H) with ammonia as describedin Sianesi et al., 1971, Chem. Ber. 104:1880 and Campagna et al., 1994,Farmaco, Ed. Sci. 49:653, both of which citations are incorporatedherein by reference).

As further illustrated in Scheme 2, protected alcohols XVII can bedeprotected providing alcohols XVIII. The deprotection method depends onthe identity of the alcohol-protecting group, see e.g., the procedureslisted in Greene, T. W., Protective Groups in Organic Synthesis, 3rdedition 17-237 (1999), particularly see pages 48-49, incorporated hereinby reference. One of skill in the art will readily be able to choose theappropriate deprotection procedure. When the alcohol is protected as anether function (e.g., methoxymethyl ether), the alcohol is preferablydeprotected with aqueous or alcoholic acid. Suitable deprotectionreagents include, but are not limited to, aqueous hydrochloric acid,p-toluenesulfonic acid in methanol, pyridinium-p-toluenesulfonate inethanol, Amberlyst H-15 in methanol, boric acid inethylene-glycol-monoethylether, acetic acid in a water-tetrahydrofuranmixture, aqueous hydrochloric acid is preferred. Examples of suchprocedures are described, respectively, in Bernady et al., 1979, J. Org.Chem. 44:1438; Miyashita et al., 1977, J. Org. Chem. 42:3772; Johnstonet al, 1988, Synthesis 393; Bongini et al., 1979, Synthesis 618; andHoyer et al., 1986, Synthesis 655; Gigg et al., 1967, J. Chem. Soc. C,431; and Corey et al., 1978, J. Am. Chem. Soc. 100:1942, all of whichare incorporated herein by reference.

Scheme 3 illustrates the synthesis of halides of formula XXI, wherein m,K², R³ and R⁴ are as defined above. Alcohols of formula XX can beprepared using the synthetic methods described herein for the synthesisof alcohols XVIII. As further shown in Scheme 3, halides XXI can besynthesized from alcohols XX by halogenation as described above for thesynthesis of protected halo-alcohols XV.

Scheme 4 outlines the synthesis of compounds of formula I by reactingalcohols XVIII with halides XXI via the Williamson ether synthesis, asdiscussed above for the synthesis of mono-protected diols X. In apreferred procedure, first, a base is added to a stirred organicsolution comprising alcohols XVIII, maintained at a constant temperaturewithin the range of about 0° C. to about 80° C., preferably at aboutroom temperature. Preferably, the base is added at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. The base can be added as anorganic solution or in undiluted form. Preferably, the base has a pK_(a)of about 15 or greater. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride. Thepreferred base is lithium diisopropylamide. Suitable solvents include,but are not limited, to dimethyl sulfoxide, dichloromethane, ethers, andmixtures thereof, preferably tetrahydrofuran. After addition of thebase, the reaction mixture is adjusted to within a temperature range ofabout 0° C. to about room temperature and halides XXI are added,preferably at a rate such that the reaction-mixture temperature remainswithin about one to two degrees of the initial reaction-mixturetemperature. Halides XXI can be diluted in an organic solvent or addedin undiluted form. The resulting reaction mixture is heated at aconstant temperature within the range of about room temperature to aboutthe solvent's boiling temperature until the reaction is substantiallycomplete as determined by using an appropriate analytical method,preferably by gas chromatography. The product I can be isolated byworkup and purification.

As illustrated in Scheme 5, mono-protected diols of the formula XXIV canbe prepared from compounds XIII, wherein X, R¹, R², and R⁸ are asdefined above. In the first step, compounds XIII are converted toalcohols of the formula XXII by reduction with a suitable reducingagent. A suitable reducing agent will be selective in that it willreduce the ester function of compounds XIII (i.e, R⁸O₂C—) tohydroxymethylene (i e, HOCH₂—), without displacing leaving group X. Thechoice of reducing agent will depend on the identities of X and R⁸. Awide variety of synthetic procedures are available for selectivereduction of such esters to alcohols (e.g., see M. Hudlicky, Reductionsin Organic Chemistry, 2nd ed., 1996 pp 212-217). For exemplaryprocedures for reducing esters to alcohols with selective reducingreagents, see Brown et al 1965, J. Am. Chem. Soc. 87:5614, lithiumtrimethoxyaluminum hydride; Cerny et al., 1969, Collect. Czech. Chem.Commun. 4:1025, sodium bis(2-methoxy)aluminum hydride; Nystrom et al.,1949, J. Am. Chem. 71:3245, lithium borohydride; and Brown et al., 1980,J. Org. Chem. 45: 1, lithium triethyl borohydride. The reaction can beperformed by stirring a mixture comprising compounds XIII, a reducingagent, and a suitable organic solvent at a constant temperature withinthe range of about −20° C. to about 80° C., preferably at about 0° C. toabout room temperature. Solvents suitable for reducing compounds XIIIinclude, but are not limited to, methanol, ethanol, isopropanol,dichloromethane, toluene, diethyl ether, tetrahydrofuran or mixturesthereof. The preferred reducing agent is lithium borohydride and thepreferred solvent is methanol. The reaction's progress is followed byusing an appropriate analytical method, preferably thin-layerchromatography or high-performance liquid chromatography, and, whencomplete, the reaction mixture can be quenched and the product can beisolated by workup and purification. Next in Scheme 5, the hydroxymoiety of alcohols XXII is protected with a hydroxyl-protecting groupproviding protected alcohols of the formula XXIII. Preferably, theprotecting group is stable to base but labile under acidic conditions.Examples of suitable base-stable, acid-labile alcohol-protecting groupsinclude, but are not limited to, ethers, such as methyl, methoxy methyl,methylthiomethyl, methoxyethoxymethyl, bis(2-chloroethoxy)methyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahyrofuranyl,tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl,allyl, benzyl, o-nitrobenzyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl; and esters,such as pivaloate, adamantoate, and 2,4,6-trimethylbenzoate. Ethers arepreferred, particularly cyclic ethers, such as tetrahydropyranyl. Forexample, when —PG is tetrahydropyranyl, protected alcohols XXIII can beprepared by contacting a stirred solution comprising alcohols XXII, anorganic solvent, and an acid catalyst with dihydropyran. Preferably, thereaction mixture is stirred for about 1 to about 24 hours, morepreferably about 2 to about 10 hours, at a temperature within thetemperature range of about 0° C. to about 50° C., preferably at aboutroom temperature. Suitable solvents include, but are not limited to,dichloromethane, hexane, toluene, tetrahydrofuran, acetonitrile, andmixtures thereof. Suitable acids include, but are not limited to,p-toluenesulfonic acid, pyridinium-p-toluene sulfonate, MgBr₂-etherate,and alumina. The reaction's progress can be followed by a suitableanalytical technique (preferably thin-layer chromatography orhigh-performance liquid chromatography) and when the reaction is deemedsubstantially complete, protected alcohols XXIII can be isolated byworkup and purification. Exemplary procedures for protecting a hydroxygroup as the tetrahydropyranyl ether can be found in Bernady et al,1979, J. Org. Chem. 44:1438; Miyashita et al., 1977, J. Org. Chem.42:3772; Johnston et al, 1988, Synthesis 393; Bongini et al., 1979,Synthesis 618 and Hoyer et al., 1986, Synthesis 655, all of which areincorporated herein by reference. As further shown in Scheme 5,mono-protected diols XXIV can be synthesized by reacting an organicsolution of protected alcohols XXIII, with about 1 to about 5equivalents of a hydroxide source. Preferably, the reaction mixture ismaintained within a temperature range of about room temperature to about110° C., more preferably about 70° C. to about 90° C., preferably forabout 1 to about 24 hours, more preferably for about 2 to about 5 hours.The reaction's progress can be followed by using an appropriateanalytical technique (such as, thin-layer chromatography orhigh-performance liquid chromatography) and, when substantiallycomplete, the product can be isolated by workup and purification. For adiscussion of hydrolysis of alkylhalides with hydroxide see March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 370, incorporated herein by reference. Suitable hydroxidesources include, but are not limited to, sodium carbonate, potassiumcarbonate, calcium carbonate, sodium hydroxide, and potassium hydroxide,preferably sodium carbonate. Suitable solvents include, but are notlimited to, dimethyl sulfoxide, dimethyl formamide,hexamethylphosphoramide, and N-methyl-2-pyrrolidone, and mixturesthereof, preferably dimethyl sulfoxide. When the solvent ishexamethylphosphoramide or N-methyl-2-pyrrolidone, water can serve asthe hydroxide source (see e.g., Kurz et al., 1985, Isr. J. Chem. 26:339and Kurz et al., 1986, J. Am. Chem. 108:2960, both of which areincorporated by reference herein).

Scheme 6 shows the synthesis of protected alcohols XXVIII, whichcompounds are synthesized by the same synthetic methods described inScheme 5 for protected alcohols XXIII.

Scheme 7 illustrates the synthesis of compounds of formula I, wherein nand m are both 0 and K¹ and K² are both —CH₂OH and R¹, R², R³, and R⁴are defined as above. The synthesis can be carried out by reactingmono-protected diols XXIV with protected alcohols XXVIII via theWilliamson ether synthesis using the synthetic procedure of Scheme 4,providing di-protected diols of the formula XXIX. Di-protected diolsXXIX can be deprotected providing compounds of formula I, wherein n andin are both 0 and K¹ and K² are both —CH₂OH, by using the syntheticdeprotection methodology described above in Scheme 1 for thedeprotection of protected alcohols XVII.

Scheme 8 illustrates homologation of compounds of formula I, wherein nand m are both 0 and K¹ and K² are both —CH₂OH to provide compounds offormula I, wherein n and m are identical integers ranging from 1 to 5.Scheme 8 involves a three step homologation sequence comprising (a)halogenation (converting CH₂OH to —CH₂-Hal), (b) carbonylation(replacing -Hal with —CHO), and (c) reduction (converting —CHO to—CH₂OH) using the same synthetic procedure discussed for thehomologation of mono-protected diols X in Scheme 1.

Scheme 9 outlines the synthesis of compounds of the formula I, whereinK¹ and K² are both —CH₂OH and R¹, R², R³, R⁴, n, and m are defined asabove, by reducing compounds XXX, wherein R¹⁰ is independently selectedfrom the group consisting of —H, —OH, (C₁-C₆)alkoxy, (C₆)aryloxy,—O(C₂-C₆)alkenyl, —OC₂-C₆)alkynyl, and halo, with a reducing agent in asuitable organic solvent. For a discussion of procedures and referencesconcerning reduction of compounds XXX see March, J. Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. 1212(R¹⁰ is —OH); p. 910 (R¹⁰ is —H); p. 1214 (R¹⁰ is (C₁-C₆)alkoxy,(C₆)aryloxy, —OXC₂-C₆)alkenyl, or —O—(C₂-C₆)alkynyl); p. 446 (R¹⁰ is-halo), incorporated herein by reference. Suitable reducing agentsinclude, but are not limited to, hydrogen (via catalytic hydrogenation);borane; allane; and hydride reducing agents, such as lithium aluminumhydride, diisobutylaluminum hydride, and sodium borohydride. When thereducing agent is a hydride reducing agent; allane; or borane, thenafter reacting XXX with the reducing agent, the intermediate salt, ifformed, is hydrolyzed with an aqueous proton source, such as dilute(e.g., 1 molar) hydrochloric acid. Suitable organic solvents include,but are not limited to, toluene, alcohols, dichloromethane, diethylether, tetrahydrofuran or mixtures thereof. Preferably, the reduction isconducted by adding an organic solution of compounds XXX to a stirredmixture comprising a hydride reducing agent, preferably lithium aluminumhydride and an organic solvent, preferably tetrahydrofuran. During theaddition, the reaction mixture is maintained at a constant temperaturewithin the range of about −20° C. to about 80° C., preferably at aboutroom temperature. After the addition, the reaction mixture is stirred ata constant temperature within the range of about room temperature toabout 60° C., until the reaction is substantially complete as determinedby using an appropriate analytical method, preferably thin-layerchromatography or high-performance-liquid chromatography. Then thereaction mixture can be quenched and compounds of the formula 1, whereinK¹ and K² are both —CH₂OH, can be isolated by workup and purification.

In another embodiment, compounds of formula 1, wherein K¹ and K² areboth —CH₂OH, can be oxidized to synthesize compounds of formula XXXwherein R¹⁰ is —OH by using an oxidizing agent, for example, anoxidizing agent suitable for oxidizing a primary alcohol to a carboxylicacid (for a discussion see M. Hudlicky, Oxidations in Organic Chemistry,ACS Monograph 186, 1990, pp. 127-130). Suitable oxidizing agentsinclude, but are not limited to, chromic acid, pyridinium dichromate(Corey et al., 1979, Tetrahedron Lett. 399); manganese dioxide (Ahrenset al., 1967, J. Heterocycl. Chem. 4:625); sodium permanganatemonohydrate (Menger et al., 1981, Tetrahedron Lett. 22:1655); andpotassium permanganate (Sam et al., 1972, J. Am. Chem. Soc. 94:4024).The preferred oxidizing reagent is pyridinium dichromate.

In another embodiment, the invention relates to compounds of formula XL

wherein:

X is a heteroatom selected from oxygen, sulfur and nitrogen, preferablyoxygen;

s and r are integers ranging from 1 to 3;

p and q are integers ranging from 2 to 9, preferably 2-5, morepreferably 4-5;

R¹¹, R¹², R¹³ and R¹⁴ are independent (C₁-C₈)hydrocarbyl groups.Preferably, (C₁-C₈)hydrocarbyl is selected from the group consisting of(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or R¹, R², and the carbonto which they are attached are taken together to form a(C₃-C₆)cycloalkyl group; or R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₆)cycloalkyl group; or R¹,R², and the carbon to which they are attached are taken together to forma (C₃-C₆)cycloalkyl group and R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₆)cycloalkyl group; and

R¹⁵ and R¹⁶ are independent(C₁-C₈)hydrocarbyl groups, or both R¹⁵ andR¹⁶ are H. Preferably, (C₁-C₈)hydrocarbyl is selected from the groupconsisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, which(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl groups may be substitutedwith one or two groups selected from halo, hydroxy, (C₁-C₆)alkoxy, andphenyl. Preferably, both R¹⁵ and R¹⁶ are H.

In yet another embodiment, the invention relates to compounds of theformula XLI

or pharmaceutically acceptable salts thereof, wherein:

s and r are integers ranging from 1 to 3;

R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently represent an unsubstituted orsubstituted hydrocarbyl group or a heterocyclic radical;

R¹¹, R¹², R¹³ and R¹⁴ are independently selected from the groupconsisting of hydrogen, lower alkyl, halogen, cyano, carboxy, loweralkoxycarbonyl and carbamoyl, preferably hydrogen, lower alkyl, fluoro,chloro, bromo, and cyano; and

R¹⁵ and R¹⁶ are independent (C₁-C₈)hydrocarbyl groups, or both R¹⁵ andR¹⁶ are H. Preferably, (C₁-C₈)hydrocarbyl is selected from the groupconsisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, which(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl groups may be substitutedwith one or two groups selected from halo, hydroxy, (C₁-C₆)alkoxy, andphenyl. Preferably, R¹⁵ and R¹⁶ are both H.

Q represents a diradical consisting of a linear chain of 8 to 14 carbonatoms, one or more of which may be replaced by heteroatoms, said chainbeing optionally substituted by inert substituents and one or more ofsaid carbon or heteroatom chain members optionally forming part of aring structure. Preferably, Q is of the formula —(CH2)_(n)—, wherein nin an integer ranging from 8 to 14. An “inert substituent” is a suitablesubstituent that does not negate the pharmaceutical utility of thecompound to which it is attached. If a heteroatom is present, it ispreferably O, S, or N.

Preferably, compounds of formula XLI are of the formula:

or pharmaceutically acceptable salts thereof, wherein R¹ and R³ areindependently selected from the group consisting of H, lower alkyl,fluoro, chloro, bromo, cyano, and t is an integer within the range of 8to 14.

In still another embodiment, the invention relates to compounds of theformula XLII

or pharmaceutically acceptable salts thereof, wherein:

s and r are integers ranging from 1 to 3;

R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently represent an unsubstituted orsubstituted hydrocarbyl or heterocyclic radical;

R¹¹, R¹², R¹³ and R¹⁴ each independently represents H, lower alkyl,halogen, cyano, carboxy, lower alkoxycarbonyl or carbamoyl; and

R¹⁵ and R¹⁶ are independent (C₁-C₈)hydrocarbyl groups, or both R¹⁵ andR¹⁶ are H. Preferably, (C₁-C₈)hydrocarbyl is selected from the groupconsisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, which(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl groups may be substitutedwith one or two groups selected from halo, hydroxy, (C₁-C₆)alkoxy, andphenyl. Preferably, R¹⁵ and R¹⁶ are both H.

Q represents a diradical consisting of a linear chain of 8 to 14 carbonatoms, one or more of which may be replaced by heteroatoms, said chainbeing optionally substituted by inert substituents and one or more ofsaid carbon or heteroatom chain members optionally forming part of aring structure. If a heteroatom is present, it is preferably O, S, or N.

Preferably, compounds of the formula XLII have the structure:

or pharmaceutically acceptable salts thereof, wherein:

t is an integer from within the range of 6 to 12, and R¹⁵, R¹⁶, r, and sare as defined above. The invention further contemplatespharmaceutically acceptable salts of the compounds of the formulas XL,XLI, and XLII. The compounds of the formulas XL, XLI, and XLII andpharmaceutically acceptable salts thereof, are useful in thecompositions and methods disclosed herein.

Compounds of the formula XL can be prepared according to the methodologydescribed in Schemes 1-4 above, starting from esters of the formulasXLIV and XLV

where R⁵, X, p, and q are as defined above. Esters of the formulas XLIVand XLV are available commercially (e g, Aldrich Chemical Co.,Milwaukee, Wis.) or can be prepared by well-known synthetic methods, forexample, esterification of the appropriate haloalkyl carboxylic acid(commercially available, e.g., Aldrich Chemical Co., Milwaukee, Wis.)

Compounds of the formula XLI, can be prepared according to Scheme 10below.

First, compounds of the formula XLVI are prepared from compounds XLIVand compounds XLV according to the methodology described in Schemes 1-4above. It is to be understood that some modifications of the syntheticprocedures outlined in Schemes 1-4 may be necessary, depending on theidentity of compounds XLVI, and one of ordinary skill will readily makesuch modifications. As such, the identity of Q depends on the choice ofcompounds XLIV and compounds XLV. Next, compounds of the formula XLVIIIare synthesized by Grignard reaction of compounds XLVI with compoundsXLVII (commercially available, e.g., Aldrich Chemical Co., Milwaukee,Wis.) according to the synthetic procedure described in Scheme 1 for thesynthesis of IX. Compounds of the formula XLVIII can then bephosphorylated to provide compounds XLI according to the methodologydescribed above in Scheme 2 for phosphorylation of compounds of theformula X. Note, Scheme 10 above illustrates the synthesis of compoundsXLI wherein R¹³ is the same group as R¹¹ and R¹⁴ is the same group asR¹², however, this methodology can be extended by one of ordinary skillin the art to synthesize compounds of XLI wherein R¹¹, R¹², R¹³, and R¹⁴are independent groups.

Compounds of the formula XLII can be prepared according to the syntheticmethodology illustrated in Scheme 11 below.

First, compounds of the formula XLIX can be prepared from compounds XLIVand compounds XLV according to the methodology described in Schemes 1-4above. It is to be understood that some modifications of the syntheticprocedures illustrated in Schemes 1-4 may be necessary, and one ofordinary skill will readily make such modifications. As such, theidentity of Q depends on the choice of XLIV and XLV. Compounds XLIX canby converted to compounds L by sequential reactions withdiethylchlorophosphite and t-butyl acetate in the presence of base.Suitable procedures for conversion of XLIX into L can be found in LarockComprehensive Organic Transformations; Wiley-VCH: New York, 1999, pp.102; particularly Song et al, 1999, J. Org. Chem. 64:9658. Compounds Lcan be converted to compounds LII by organometallic addition ofR¹¹⁻¹⁴-M, where M is defined as in Scheme 1, to the ester function of L,using the methodology illustrated in Scheme 1 for the synthesis ofcompounds IX. Compounds of the formula LII can then be phosphorylated toprovide compounds XLII according to the phosphorylation methodologyillustrated in Scheme 2 above for phosphorylation of compounds of theformula X.

5.4. Therapeutic Uses of the Compounds of the Invention

In accordance with the invention, a composition of the invention,comprising a compound of the invention and a pharmaceutically acceptablevehicle, is administered to a patient, preferably a human, with acardiovascular disease, a dyslipidemia, a dyslipoproteinemia, a disorderof glucose metabolism, Alzheimer's Disease, Syndrome X, aPPAR-associated disorder, septicemia, a thrombotic disorder, obesity,pancreatitis, hypertension, a renal disease, cancer, inflammation, orimpotence. In one embodiment, “treatment” or “treating” refers to anamelioration of a disease or disorder, or at least one discerniblesymptom thereof. In another embodiment, “treatment” or “treating” refersto an amelioration of at least one measurable physical parameter, notnecessarily discernible by the patient. In yet another embodiment,“treatment” or “treating” refers to inhibiting the progression of adisease or disorder, either physically, e.g., stabilization of adiscernible symptom, physiologically, e.g., stabilization of a physicalparameter, or both. In yet another embodiment, “treatment” or “treating”refers to delaying the onset of a disease or disorder.

In certain embodiments, the compositions of the invention areadministered to a patient, preferably a human, as a preventative measureagainst such diseases. As used herein, “prevention” or “preventing”refers to a reduction of the risk of acquiring a given disease ordisorder. In a preferred mode of the embodiment, the compositions of thepresent invention are administered as a preventative measure to apatient, preferably a human having a genetic predisposition to acardiovascular disease, a dyslipidemia, a dyslipoproteinemia, a disorderof glucose metabolism, Alzheimer's Disease, Syndrome X, aPPAR-associated disorder, septicemia, a thrombotic disorder, obesity,pancreatitis, hypertension, a renal disease, cancer, inflammation, orimpotence. Examples of such genetic predispositions include but are notlimited to the ε4 allele of apolipoprotein E, which increases thelikelihood of Alzheimer's Disease; a loss of function or null mutationin the lipoprotein lipase gene coding region or promoter (e.g.,mutations in the coding regions resulting in the substitutions D9N andN291 S; for a review of genetic mutations in the lipoprotein lipase genethat increase the risk of cardiovascular diseases, dyslipidemias anddyslipoproteinemias, see Hayden and Ma, 1992, Mol. Cell Biochem.113:171-176); and familial combined hyperlipidemia and familialhypercholesterolemia.

In another preferred mode of the embodiment, the compositions of theinvention are administered as a preventative measure to a patient havinga non-genetic predisposition to a cardiovascular disease, adyslipidemia, a dyslipoproteinemia, a disorder of glucose metabolism,Alzheimer's Disease, Syndrome X, a PPAR-associated disorder, septicemia,a thrombotic disorder, obesity, pancreatitis, hypertension, a renaldisease, cancer, inflammation, or impotence. Examples of suchnon-genetic predispositions include but are not limited to cardiacbypass surgery and percutaneous transluminal coronary angioplasty, whichoften lead to restenosis, an accelerated form of atherosclerosis;diabetes in women, which often leads to polycystic ovarian disease; andcardiovascular disease, which often leads to impotence. Accordingly, thecompositions of the invention may be used for the prevention of onedisease or disorder and concurrently treating another (e.g., preventionof polycystic ovarian disease while treating diabetes; prevention ofimpotence while treating a cardiovascular disease).

5.4.1. Cardiovascular Diseases for Treatment or Prevention

The present invention provides methods for the treatment or preventionof a cardiovascular disease, comprising administering to a patient atherapeutically effective amount of a composition comprising a compoundof the invention and a pharmaceutically acceptable vehicle. As usedherein, the term “cardiovascular diseases” refers to diseases of theheart and circulatory system. These diseases are often associated withdyslipoproteinemias and/or dyslipidemias. Cardiovascular diseases whichthe compositions of the present invention are useful for preventing ortreating include but are not limited to arteriosclerosis;atherosclerosis; stroke; ischemia; endothelium dysfunctions, inparticular those dysfunctions affecting blood vessel elasticity;peripheral vascular disease; coronary heart disease; myocardialinfarcation; cerebral infarction and restenosis.

5.4.2. Dyslipidemias for Treatment or Prevention

The present invention provides methods for the treatment or preventionof a dyslipidemia comprising administering to a patient atherapeutically effective amount of a composition comprising a compoundof the invention and a pharmaceutically acceptable vehicle.

As used herein, the term “dyslipidemias” refers to disorders that leadto or are manifested by aberrant levels of circulating lipids. To theextent that levels of lipids in the blood are too high, the compositionsof the invention are administered to a patient to restore normal levels.Normal levels of lipids are reported in medical treatises known to thoseof skill in the art. For example, recommended blood levels of LDL, HDL,free triglycerides and others parameters relating to lipid metabolismcan be found at the web site of the American Heart Association and thatof the National Cholesterol Education Program of the National Heart,Lung and Blood Institute (http://www.americanheart.org andhttp://rover.nhlbi.nih.vov/chd/, respectively). At the present time, therecommended level of HDL cholesterol in the blood is above 35 mg/dL; therecommended level of LDL cholesterol in the blood is below 130 mg/dL;the recommended LDL:HDL cholesterol ratio in the blood is below 5:1,ideally 3.5:1; and the recommended level of free triglycerides in theblood is less than 200 mg/dL.

Dyslipidemias which the compositions of the present invention are usefulfor preventing or treating include but are not limited to hyperlipidemiaand low blood levels of high density lipoprotein (HDL) cholesterol. Incertain embodiments, the hyperlipidemia for prevention or treatment bythe compounds of the present invention is familial hypercholesterolemia;familial combined hyperlipidemia; reduced or deficient lipoproteinlipase levels or activity, including reductions or deficienciesresulting from lipoprotein lipase mutations; hypertriglyceridemia;hypercholesterolemia; high blood levels of ketone bodies (e.g. β-OHbutyric acid); high blood levels of Lp(a) cholesterol; high blood levelsof low density lipoprotein (LDL) cholesterol; high blood levels of verylow density lipoprotein (VLDL) cholesterol and high blood levels ofnon-esterified fatty acids.

The present invention further provides methods for altering lipidmetabolism in a patient, e.g., reducing LDL in the blood of a patient,reducing free triglycerides in the blood of a patient, increasing theratio of HDL to LDL in the blood of a patient, and inhibiting saponifiedand/or non-saponified fatty acid synthesis, said methods comprisingadministering to the patient a composition comprising a compound of theinvention in an amount effective alter lipid metabolism.

5.4.3. Dyslipoproteinemias for Treatment or Prevention

The present invention provides methods for the treatment or preventionof a dyslipoproteinemia comprising administering to a patient atherapeutically effective amount of a composition comprising a compoundof the invention and a pharmaceutically acceptable vehicle.

As used herein, the term “dyslipoproteinemias” refers to disorders thatlead to or are manifested by aberrant levels of circulatinglipoproteins. To the extent that levels of lipoproteins in the blood aretoo high, the compositions of the invention are administered to apatient to restore normal levels. Conversely, to the extent that levelsof lipoproteins in the blood are too low, the compositions of theinvention are administered to a patient to restore normal levels. Normallevels of lipoproteins are reported in medical treatises known to thoseof skill in the art.

Dyslipoproteinemias which the compositions of the present invention areuseful for preventing or treating include but are not limited to highblood levels of LDL; high blood levels of apolipoprotein B (apo B); highblood levels of Lp(a); high blood levels of apo(a); high blood levels ofVLDL; low blood levels of HDL; reduced or deficient lipoprotein lipaselevels or activity, including reductions or deficiencies resulting fromlipoprotein lipase mutations; hypoalphalipoproteinemia; lipoproteinabnormalities associated with diabetes; lipoprotein abnormalitiesassociated with obesity; lipoprotein abnormalities associated withAlzheimer's Disease; and familial combined hyperlipidemia.

The present invention further provides methods for reducing apo C-IIlevels in the blood of a patient; reducing apo C-III levels in the bloodof a patient; elevating the levels of HDL associated proteins, includingbut not limited to apo A-I, apo A-II, apo A-IV and apo E in the blood ofa patient; elevating the levels of apo E in the blood of a patient, andpromoting clearance of triglycerides from the blood of a patient, saidmethods comprising administering to the patient a composition comprisinga compound of the invention in an amount effective to bring about saidreduction, elevation or promotion, respectively.

5.4.4. Glucose Metabolism Disorders for Treatment or Prevention

The present invention provides methods for the treatment or preventionof a glucose metabolism disorder, comprising administering to a patienta therapeutically effective amount of a composition comprising acompound of the invention and a pharmaceutically acceptable vehicle. Asused herein, the term “glucose metabolism disorders” refers to disordersthat lead to or are manifested by aberrant glucose storage and/orutilization. To the extent that indicia of glucose metabolism (i.e.,blood insulin, blood glucose) are too high, the compositions of theinvention are administered to a patient to restore normal levels.Conversely, to the extent that indicia of glucose metabolism are toolow, the compositions of the invention are administered to a patient torestore normal levels. Normal indicia of glucose metabolism are reportedin medical treatises known to those of skill in the art.

Glucose metabolism disorders which the compositions of the presentinvention are useful for preventing or treating include but are notlimited to impaired glucose tolerance; insulin resistance; insulinresistance related breast, colon or prostate cancer; diabetes, includingbut not limited to non-insulin dependent diabetes mellitus (NIDDM),insulin dependent diabetes mellitus (IDDM), gestational diabetesmellitus (GDM), and maturity onset diabetes of the young (MODY);pancreatitis; hypertension; polycystic ovarian disease; and high levelsof blood insulin and/or glucose.

The present invention further provides methods for altering glucosemetabolism in a patient, for example to increase insulin sensitivityand/or oxygen consumption of a patient, said methods comprisingadministering to the patient a composition comprising a compound of theinvention in an amount effective to alter glucose metabolism.

5.4.5. PPAR Associated Disorders for Treatment or Prevention

The present invention provides methods for the treatment or preventionof a PPAR-associated disorder, comprising administering to a patient atherapeutically effective amount of a composition comprising a compoundof the invention and a pharmaceutically acceptable vehicle. As usedherein, “treatment or prevention of PPAR associated disorders”encompasses treatment or prevention of rheumatoid arthritis; multiplesclerosis; psoriasis; inflammatory bowel diseases; breast; colon orprostate cancer; low levels of blood HDL; low levels of blood, lymphand/or cerebrospinal fluid apo E; low blood, lymph and/or cerebrospinalfluid levels of apo A-I; high levels of blood VLDL; high levels of bloodLDL; high levels of blood triglyceride; high levels of blood apo B; highlevels of blood apo C-III and reduced ratio of post-heparin hepaticlipase to lipoprotein lipase activity. HDL may be elevated in lymphand/or cerebral fluid.

5.4.6. Renal Diseases for Treatment or Prevention

The present invention provides methods for the treatment or preventionof a renal disease, comprising administering to a patient atherapeutically effective amount of a composition comprising a compoundof the invention and a pharmaceutically acceptable vehicle. Renaldiseases that can be treated by the compounds of the present inventioninclude glomerular diseases (including but not limited to acute andchronic glomerulonephritis, rapidly progressive glomerulonephritis,nephrotic syndrome, focal proliferative glomerulonephritis, glomerularlesions associated with systemic disease, such as systemic lupuserythematosus, Goodpasture's syndrome, multiple myeloma, diabetes,neoplasia, sickle cell disease and chronic inflammatory diseases),tubular diseases (including but not limited to acute tubular necrosisand acute renal failure, polycystic renal diseasemedullary spongekidney, medullary cystic disease, nephrogenic diabetes, and renaltubular acidosis), tubulointerstitial diseases (including but notlimited to pyelonephritis, drug and toxin induced tubulointerstitialnephritis, hypercalcemic nephropathy, and hypokalemic nephropathy) acuteand rapidly progressive renal failure, chronic renal failure,nephrolithiasis, or tumors (including but not limited to renal cellcarcinoma and nephroblastoma). In a most preferred embodiment, renaldiseases that are treated by the compounds of the present invention arevascular diseases, including but not limited to hypertension,nephrosclerosis, microangiopathic hemolytic anemia, atheroembolic renaldisease, diffuse cortical necrosis, and renal infarcts.

5.4.7. Cancers for Treatment or Prevention

The present invention provides methods for the treatment or preventionof cancer, comprising administering to a patient a therapeuticallyeffective amount of a composition comprising a compound of the inventionand a pharmaceutically acceptable vehicle. Cancers that can be treatedor prevented by administering the compounds of the invention include,but are not limited to, human sarcomas and carcinomas, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyclocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavychain disease. In a most preferred embodiment, cancers that are treatedor prevented by administering the compounds of the present invention areinsulin resistance or Syndrome X related cancers, including but notlimited to breast, prostate and colon cancer.

5.4.8. Other Diseases for Treatment or Prevention

The present invention provides methods for the treatment or preventionof Alzheimer's Disease, Syndrome X, septicemia, thrombotic disorders,obesity, pancreatitis, hypertension, inflammation, and impotence,comprising administering to a patient a therapeutically effective amountof a composition comprising a compound of the invention and apharmaceutically acceptable vehicle.

As used herein, “treatment or prevention of Alzheimer's Disease”encompasses treatment or prevention of lipoprotein abnormalitiesassociated with Alzheimer's Disease.

As used herein, “treatment or prevention of Syndrome X or MetabolicSyndrome” encompasses treatment or prevention of a symptom thereof,including but not limited to impaired glucose tolerance, hypertensionand dyslipidemia/dyslipoproteinemia.

As used herein, “treatment or prevention of septicemia” encompassestreatment or prevention of septic shock.

As used herein, “treatment or prevention of thrombotic disorders”encompasses treatment or prevention of high blood levels of fibrinogenand promotion of fibrinolysis.

In addition to treating or preventing obesity, the compositions of theinvention can be administered to an individual to promote weightreduction of the individual.

5.5. Surgical Uses of the Compounds of the Invention

Cardiovascular diseases such as atherosclerosis often require surgicalprocedures such as angioplasty. Angioplasty is often accompanied by theplacement of a reinforcing a metallic tube-shaped structure known as a“stent” into a damaged coronary artery. For more serious conditions,open heart surgery such as coronary bypass surgery may be required.These surgical procedures entail using invasive surgical devices and/orimplants, and are associated with a high risk of restenosis andthrombosis. Accordingly, the compounds of the invention may be used ascoatings on surgical devices (e.g., catheters) and implants (e.g.,stents) to reduce the risk of restenosis and thrombosis associated withinvasive procedures used in the treatment of cardiovascular diseases.

5.6. Veterinary and Livestock Uses of the Compounds of the Invention

A composition of the invention can be administered to a non-human animalfor a veterinary use for treating or preventing a disease or disorderdisclosed herein.

In a specific embodiment, the non-human animal is a household pet. Inanother specific embodiment, the non-human animal is a livestock animal.In a preferred embodiment, the non-human animal is a mammal, mostpreferably a cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit, orguinea pig. In another preferred embodiment, the non-human animal is afowl species, most preferably a chicken, turkey, duck, goose, or quail.

In addition to veterinary uses, the compounds of the invention can beused to reduce the fat content of livestock to produce leaner meats.Alternatively, the compounds of the invention can be used to reduce thecholesterol content of eggs by administering the compounds to a chicken,quail, or duck hen. For non-human animal uses, the compounds of theinvention can be administered via the animals' feed or orally as adrench composition.

5.7. Therapeutic/Prophylactic Administration and Compositions

Due to the activity of the compounds of the invention, the compounds areadvantageously useful in veterinary and human medicine. As described inSection 5.3 above, the compounds of the invention are useful for thetreatment or prevention of cardiovascular diseases, dyslipidemias,dyslipoproteinemias, glucose metabolism disorders, Alzheimer's Disease,Syndrome X, PPAR-associated disorders, septicemia, thrombotic disorders,obesity, pancreatitis, hypertension, renal disease, cancer,inflammation, and impotence.

The invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acomposition comprising a compound of the invention. The patient is ananimal, including, but not limited, to an animal such a cow, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guineapig, etc., and is more preferably a mammal, and most preferably a human.

The present compositions, which comprise one or more compounds of theinvention, are preferably administered orally. The compounds of theinvention may also be administered by any other convenient route, forexample, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.) and may be administered together with anotherbiologically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc., and can be used toadminister a compound of the invention. In certain embodiments, morethan one compound of the invention is administered to a patient. Methodsof administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The preferred mode of administration is leftto the discretion of the practitioner, and will depend in-part upon thesite of the medical condition. In most instances, administration willresult in the release of the compounds of the invention into thebloodstream.

In specific embodiments, it may be desirable to administer one or morecompounds of the invention locally to the area in need of treatment.This may be achieved, for example, and not by way of limitation, bylocal infusion during surgery, topical application, e.g., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, saidimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers. In one embodiment,administration can be by direct injection at the site (or former site)of an atherosclerotic plaque tissue.

In certain embodiments, for example, for the treatment of Alzheimer'sDisease, it may be desirable to introduce one or more compounds of theinvention into the central nervous system by any suitable route,including intraventricular, intrathecal and epidural injection.Intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of the invention can be formulated asa suppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the compounds of the invention can be deliveredin a vesicle, in particular a liposome (see Langer, 1990, Science249:1527-1533; Treat et al., in Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York,pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.).

In yet another embodiment, the compounds of the invention can bedelivered in a controlled release system. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit. Ref Biomed Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engi J. Med 321:574). In another embodiment, polymeric materials can beused (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 711:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of the target of the compounds of theinvention, e.g., the liver, thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, in Medical Applications of ControlledRelease, supra, vol. 2, pp. 115-138 (1984)). Other controlled-releasesystems discussed in the review by Langer, 1990, Science 249:1527-1533)may be used.

The present compositions will contain a therapeutically effective amountof a compound of the invention, optionally more than one compound of theinvention, preferably in purified form, together with a suitable amountof a pharmaceutically acceptable vehicle so as to provide the form forproper administration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “vehicle” refers to a diluent, adjuvant, excipient, or carrier withwhich a compound of the invention is administered. Such pharmaceuticalvehicles can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalvehicles can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.When administered to a patient, the compounds of the invention andpharmaceutically acceptable vehicles are preferably sterile. Water is apreferred vehicle when the compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in “Remington's PharmaceuticalSciences” by E. W. Martin.

In a preferred embodiment, the compounds of the invention are formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous administration to human beings. Typically,compounds of the invention for intravenous administration are solutionsin sterile isotonic aqueous buffer. Where necessary, the compositionsmay also include a solubilizing agent. Compositions for intravenousadministration may optionally include a local anesthetic such aslignocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the compound ofthe invention is to be administered by infusion, it can be dispensed,for example, with an infusion bottle containing sterile pharmaceuticalgrade water or saline. Where the compound of the invention isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions maycontain one or more optionally agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions may be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to 200 milligrams ofa compound of the invention per kilogram body weight. In specificpreferred embodiments of the invention, the oral dose is 0.01 milligramto 70 milligrams per kilogram body weight, more preferably 0.1 milligramto 50 milligrams per kilogram body weight, more preferably 0.5 milligramto 20 milligrams per kilogram body weight, and yet more preferably 1milligram to 10 milligrams per kilogram body weight. In a most preferredembodiment, the oral dose is 5 milligrams of a compound of the inventionper kilogram body weight. The dosage amounts described herein refer tototal amounts administered; that is, if more than one compound of theinvention is administered, the preferred dosages correspond to the totalamount of the compounds of the invention administered. Oral compositionspreferably contain 10% to 95% active ingredient by weight.

Suitable dosage ranges for intravenous (i.v.) administration are 0.01milligram to 100 milligrams per kilogram body weight, 0.1 milligram to35 milligrams per kilogram body weight, and 1 milligram to 10 milligramsper kilogram body weight. Suitable dosage ranges for intranasaladministration are generally about 0.01 pg/kg body weight to 1 mg/kgbody weight. Suppositories generally contain 0.01 milligram to 50milligrams of a compound of the invention per kilogram body weight andcomprise active ingredient in the range of 0.5% to 10% by weight.Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of 0.001 milligram to 200 milligrams per kilogram of body weight.Suitable doses of the compounds of the invention for topicaladministration are in the range of 0.001 milligram to 1 milligram,depending on the area to which the compound is administered. Effectivedoses may be extrapolated from dose-response curves derived from invitro or animal model test systems. Such animal models and systems arewell known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In a certain embodiment, the kit contains more than onecompound of the invention. In another embodiment, the kit comprises acompound of the invention and another lipid-mediating compound,including but not limited to a statin, a thiazolidinedione, or afibrate.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is preferred for lowering fatty acidsynthesis. The compounds of the invention may also be demonstrated to beeffective and safe using animal model systems.

Other methods will be known to the skilled artisan and are within thescope of the invention.

5.8. Combination Therapy

In certain embodiments of the present invention, the compounds of theinvention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compound of theinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition asthe compound of the invention or a different composition. In anotherembodiment, a composition comprising a compound of the invention isadministered prior or subsequent to administration of anothertherapeutic agent. As many of the disorders for which the compounds ofthe invention are useful in treating are chronic disorders, in oneembodiment combination therapy involves alternating betweenadministering a composition comprising a compound of the invention and acomposition comprising another therapeutic agent, e.g., to minimize thetoxicity associated with a particular drug. The duration ofadministration of each drug or therapeutic agent can be, e.g., onemonth, three months, six months, or a year. In certain embodiments, whena composition of the invention is administered concurrently with anothertherapeutic agent that potentially produces adverse side effectsincluding but not limited to toxicity, the therapeutic agent canadvantageously be administered at a dose that falls below the thresholdat which the adverse side is elicited.

The present compositions can be administered together with a statin.Statins for use in combination with the compounds of the inventioninclude but are not limited to atorvastatin, pravastatin, fluvastatin,lovastatin, simvastatin, and cerivastatin.

The present compositions can also be administered together with a PPARagonist, for example a thiazolidinedione or a fibrate.Thiazolidinediones for use in combination with the compounds of theinvention include but are not limited to5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,troglitazone, pioglitazone, ciglitazone, WAY-120,744, englitazone, AD5075, darglitazone, and rosiglitazone. Fibrates for use in combinationwith the compounds of the invention include but are not limited togemfibrozil, fenofibrate, clofibrate, or ciprofibrate. As mentionedpreviously, a therapeutically effective amount of a fibrate orthiazolidinedione often has toxic side effects. Accordingly, in apreferred embodiment of the present invention, when a composition of theinvention is administered in combination with a PPAR agonist, the dosageof the PPAR agonist is below that which is accompanied by toxic sideeffects.

The present compositions can also be administered together with abile-acid-binding resin. Bile-acid-binding resins for use in combinationwith the compounds of the invention include but are not limited tocholestyramine and colestipol hydrochloride.

The present compositions can also be administered together with niacinor nicotinic acid.

The present compositions can also be administered together with a RXRagonist. RXR agonists for use in combination with the compounds of theinvention include but are not limited to LG 100268, LGD 1069, 9-cisretinoic acid,2-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl)-pyridine-5-carboxylicacid, or4-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)₂-carbonyl)-benzoicacid.

The present compositions can also be administered together with ananti-obesity drug. Anti-obesity drugs for use in combination with thecompounds of the invention include but are not limited to β-adrenergicreceptor agonists, preferably β-3 receptor agonists, fenfluramine,dexfenfluramine, sibutramine, bupropion, fluoxetine, and phentermine.

The present compositions can also be administered together with ahormone. Hormones for use in combination with the compounds of theinvention include but are not limited to thyroid hormone, estrogen andinsulin. Preferred insulins include but are not limited to injectableinsulin, transdermal insulin, inhaled insulin, or any combinationthereof. As an alternative to insulin, an insulin derivative,secretagogue, sensitizer or mimetic may be used. Insulin secretagoguesfor use in combination with the compounds of the invention include butare not limited to forskolin, dibutryl cAMP or isobutylmethylxanthine(IBMX).

The present compositions can also be administered together with atyrophostine or an analog thereof. Tyrophostines for use in combinationwith the compounds of the invention include but are not limited totryophostine 51.

The present compositions can also be administered together withsulfonylurea-based drugs. Sulfonylurea-based drugs for use incombination with the compounds of the invention include, but are notlimited to, glisoxepid, glyburide, acetohexamide, chlorpropamide,glibornuride, tolbutamide, tolazamide, glipizide, gliclazide,gliquidone, glyhexamide, phenbutamide, and tolcyclamide.

The present compositions can also be administered together with abiguamide. Biguamides for use in combination with the compounds of theinvention include but are not limited to metformin, phenformin andbuformin.

The present compositions can also be administered together with anα-glucosidase inhibitor. α-glucosidase inhibitors for use in combinationwith the compounds of the invention include but are not limited toacarbose and miglitol.

The present compositions can also be administered together with an apoA-I agonist. In one embodiment, the apo A-I agonist is the Milano formof apo A-I (apo A-IM). In a preferred mode of the embodiment, the apoA-IM for administration in conjunction with the compounds of theinvention is produced by the method of U.S. Pat. No. 5,721,114 toAbrahamsen. In a more preferred embodiment, the apo A-I agonist is apeptide agonist. In a preferred mode of the embodiment, the apo A-Ipeptide agonist for administration in conjunction with the compounds ofthe invention is a peptide of U.S. Pat. Nos. 6,004,925 or 6,037,323 toDasseux.

The present compositions can also be administered together withapolipoprotein E (apo E). In a preferred mode of the embodiment, theapoE for administration in conjunction with the compounds of theinvention is produced by the method of U.S. Pat. No. 5,834,596 toAgeland.

In yet other embodiments, the present compositions can be administeredtogether with an HDL-raising drug; an HDL enhancer; or a regulator ofthe apolipoprotein A-I, apolipoprotein A-IV and/or apolipoprotein genes.

5.8.1. Combination Therapy with Cardiovascular Drugs

The present compositions can be administered together with a knowncardiovascular drug. Cardiovascular drugs for use in combination withthe compounds of the invention to prevent or treat cardiovasculardiseases include but are not limited to peripheral antiadrenergic drugs,centrally acting antihypertensive drugs (e.g., methyldopa, methyldopaHCl), antihypertensive direct vasodilators (e.g., diazoxide, hydralazineHCl), drugs affecting renin-angiotensin system, peripheral vasodilators,phentolamine, antianginal drugs, cardiac glycosides, inodilators (e.g.,amrinone, milrinone, enoximone, fenoximone, imazodan, sulmazole),antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan, andrezulin.

5.8.2. Combination Therapy for Cancer Treatment

The present compositions can be administered together with treatmentwith irradiation or one or more chemotherapeutic agents. For irridiationtreatment, the irradiation can be gamma rays or X-rays. For a generaloverview of radiation therapy, see Hellman, Chapter 12: Principles ofRadiation Therapy Cancer, in: Principles and Practice of Oncology,DeVita et al., eds., 2^(nd). Ed., J. B. Lippencott Company,Philadelphia. Useful chemotherapeutic agents include methotrexate,taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine,cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin,mitomycin, dacarbazine, procarbizine, etoposides, campathecins,bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin,plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine,vinorelbine, paclitaxel, and docetaxel. In a specific embodiment, acomposition of the invention further comprises one or morechemotherapeutic agents and/or is administered concurrently withradiation therapy. In another specific embodiment, chemotherapy orradiation therapy is administered prior or subsequent to administrationof a present composition, preferably at least an hour, five hours, 12hours, a day, a week, a month, more preferably several months (e.g., upto three months), subsequent to administration of a composition of theinvention.

6. EXAMPLE Synthesis of Compound A 6.1. Method A

In a three neck 2 liter round bottom flask fitted with a droppingfunnel, thermometer, condenser with HCl trap and mechanical stirrer,146.2 g (2 mol) of tetrahydrofuran (THF) and 102.4 g (0.66 mol) ofphosphorus oxychloride were carefully added through the dropping funnel.To the well stirred mixture, 20 ml H₂SO₄ were added cautiously, and thetemperature was brought to 85° C. with an oil bath, then the heating wasstopped. After approximately 20 minutes, the temperature rose to 100° C.A strong exothermic reaction then occurred and the temperature rose to140° C. The color of the reaction mixture turned brown and the evolutionof HCl was violent. When the addition was complete (no more gasevolution), the reaction mixture was left to reach 70° C., and 200 mltap water was added. The mixture was heated at reflux for 30 minutes,and the unreacted THF and the 1,4-dichlorobutane formed as byproductwere removed by azeotropic distillation at atmospheric pressure. Thedistillation residue was separated in a separatory funnel into an oilylayer (the product) and an aqueous layer, which was treated with 200 mlwater, then extracted with ether (3×150 ml). The combined organicfractions were washed with sodium bicarbonate 5% (2×150 ml), saturatedaqueous ammonium chloride (1×150 ml), dried anhydrous Na₂SO₄, and thesolvent was evaporated in the vacuum. The crude product was distilledunder reduced pressure. The main fraction was 83.2 g at 83° to 87° C.(0.4-0.6 mm) at 90% purity. Yield of bis(4-chlorobutyl) ether was 56%.

4,4-Dichlorobutyl ether (40 g, 0.2 mol), sodium iodide (67 g, excess)and 500 ml acetone was added to a 3-neck 1-L round bottom flask fittedcondenser with a calcium chloride trap and magnetic stirrer. The mixturewas heated under reflux for seven days, while the color of the reactionmixture turned yellow. The reaction mixture was then filtered, and theacetone was removed in vacuo. The residue was washed with water (2×100ml), dried (anhydrous CaCl₂), and the crude product was filtered fromthe drying agent, to give 77 g of bis(4-iodobutyl)ether of ca. 80%purity. Yield ca. 80%.

THF (150 ml) and ethyl isobutyrate (17.4 g, 22 ml, 0.15 mol) were addedunder argon to a 1-L 3 neck round bottom flask fitted with a condenser,a dropping funnel, pressure equalizer, and a magnetic stirrer. Themixture was then cooled to −78° C. A solution of LDA (75 ml, 2.0 MnTHF/heptane) was added dropwise with a syringe. After the addition wascomplete, the reaction mixture was stirred at −78° C. for one additionalhour, then the solution of bis-(4-iodobutyl) ether (18 g, 0.05 mmol) andHMPA (10 ml) in 50 ml THF was added dropwise at −78° C. When theaddition was complete, the reaction mixture was allowed to reach roomtemperature, then was left stirring overnight.

The reaction mixture was cautiously poured onto 50 grams ice cold 20 mlconcentrated HCl, and was extracted with diethel ether (2×100 ml). Thecombined ethereal layers were dried over anhydrous sodium sulphate, thesolvent was evaporated under vacuum, and the organic residue (27 g) wasused without further purification.

Lithium aluminum hydride (4 g, 0.1 mol) and diethyl ether (250 ml) wereadded under argon to a one liter three neck round bottom argon-purgedflask fitted with a condenser, a dropping funnel pressure equalizer, anda magnetic stirrer. Bis(5-carbethoxy-5-methylhexyl)ether (15 g, 40 mmol)in diethyl ether (50 ml) was added to the solution under vigorousstirring. After the addition was complete, the reaction mixture wasstirred for one hour, then the excess lithium aluminum hydride wasdestroyed by cautious addition of water (50 ml), followed by hydrolysiswith 25% H₂SO₄ (25 ml). The reaction mixture was separated in aseparatory funnel, and the aqueous layer was extracted with diethylether (2×100 ml). The combined ethereal layers were washed with 5% aq.sodium bicarbonate (1×50 ml), saturated aq. ammonium chloride (50 ml)and finally dried over anhydrous ammonium sulfate. The solvent wasevaporated under vacuum to afford crude Compound A. 6 g of the crudeproduct was passed through silica gel and 2.8 g of Compound A (ca. 90%purity) was obtained. Yield 85%.

6.2. Method B

STEP A (Synthesis of 6-Bromo-2-ethoxycarbonyl-2-methylhexane): In a 1-L3-neck round-bottomed flask fitted with condenser, dropping funnelpressure equalizer and magnetic stirrer, purged with argon andmaintained under argon, were added ethyl isobutyrate (84 ml, 0.63 mol)and THF (120 ml). The mixture was cooled to −78° C., when a solution ofLDA (300 ml, 2.0 M in THF/heptane) was added dropwise with a syringe.After the addition was complete, the reaction mixture was stirred at−78° C. for 1 hr. To this mixture, 1,4-dibromobutane (105 ml, 0.84 mol)was added at −78° C., followed by HMPA (90 ml). The reaction mixture wasstirred for 30 min at −78° C., then the cooling was stopped. Thereaction was left to warm to room temperature, and was quenched with asaturated NH₄Cl solution (1.8 L). The aqueous layer was extracted withethyl acetate (3×100 ml), the organic extracts combined were washed withbrine (100 ml), 5% HCl (100 ml) and saturated NaHCO₃ (100 ml). Theorganic phase was dried (MgSO₄) and the solvent was evaporated undervacuum. The residue was distilled under reduced pressure to provide theabove-titled compound (105.2 g, 70%) (bp 65° C./0.15 mmHg). ¹H NMRCDCl₃, δ (ppm): 4.15 (q, J=4 Hz, 2H), 3.41 (t, J=5.3 Hz, 2H), 1.85 (qv,J=4 Hz, 2H), 1.60-1.45 (m, 2H), 1.40-1.30 (in, 2H), 1.28 (t, J=4 Hz,311), 1.20 (s, 6H); ¹³C NMR CDCl₃, δ (ppm): 177.3, 60.0, 41.8; 39.4,33.2, 32.9, 24.9, 23.34, 14.02.

STEP B (Synthesis of 6-Bromo-2,2-dimethyl-1-hydroxyhexane): In a 1-L3-neck round-bottomed flask fitted with condenser, dropping funnelpressure equalizer and magnetic stirrer were placed dry benzene (300 ml)and 6-bromo-2,2-dimethylhexanoate (40 g, 0.159 mol) under argon. To thissolution, DIBAL (400 ml as a 1M solution in hexane) was added over 45min at room temperature, via a syringe. During the addition, thetemperature rose to ca. 50° C., and when the exothermic reaction ceased,the mixture was heated to 5060° C. for an additional 4 hrs. The reactionmixture was allowed to reach room temperature and stir overnight. Theresulting mixture was treated with water (ca. 50 ml) under vigorousstirring, while cooling in an ice-bath. Diethyl ether (200 ml) was addedto facilitate the stirring. The ice bath was removed when no moreevolution of gas occurred. The reaction product, as a white sludge, wasfiltered through a fritted glass funnel and the filtrate was evaporatedunder vacuum. CHCl₃ (ca. 300 ml) was added to the resulting residue andthe resulting solution was washed with saturated aqueous NHCl₄ (200 ml)and brine (200 ml), then dried (MgSO₄). The solvent was evaporated undervacuum, to provide 27.30 g (82.2% yield) of the above-titled compound:¹H NMR CDCl₃, δ (ppm): 3.38 (t, J=7.4 Hz, 2H), 3.50-3.40 (brs, 1H, OH),3.22 (d, J=5.6 Hz, 2H), 1.85 (qv, J=7.4 Hz, 2H), 1.50-1.35 (m, 2H),1.30-1.20 (m, 2H), 0.85 (s, 6H). ¹³C NMR CDCl₃, δ (ppm): 71.4, 37.5,34.9; 33.9, 33.4, 23.7, 22.4.

STEP C (Synthesis of6-Bromo-2,2-dimethyl-1(tetrahydropyranyloxy)hexane): In a 500 mlthree-neck flask fitted with a condenser and magnetic stirrer was placedunder argon a mixture of 6-bromo-2,2-dimethyl-1-hydroxyhexane (25 g,0.119 mol), dichloromethane (300 ml) and p-toluenesulfonic acid (0.15 g,0.78 mmol). 3,4-Dihydro-2H-pyran (12.57 g, 0.1495 mol) was added slowlyto the mixture at 0° C. The reaction mixture was stirred at roomtemperature for one hour, and then the mixture was filtered throughaluminum oxide, which was further washed with dichloromethane (200 ml).The combined fractions were evaporated under vacuum to provide 33.73 g(97%) of the above-titled compound as a pale-yellow residue, ca. 90%: ¹HNMR CDCl₃, δ (ppm): 4.48-4.52 (m, 1H), 3.90-3.75 (m, 1H), 3.50-3.35 (m,414), 2.95 (d, J=12 Hz, 1H), 1.90-1.20 (m, 12H), 0.90 (s, 6H); ¹³C NMRCDCl₃, δ (ppm): 99.0, 76.2, 61.8, 38.2, 34.0, 33.8, 33.6, 30.5, 25.5,24.5, 24.4, 22.5, 19.3.

STEP D (Synthesis of2,2-Dimethyl-5-hydroxy-1(tetrahydropyranyloxy)hexane): In a 250 ml flaskequipped with a magnetical stirrer and reflux condenser were placed6-bromo-I(tetrahydropyranyloxy)-2,2-dimethylhexane (10 g, 0.034 mol) andDMSO (50 ml), then the mixture was treated with K₂CO₃ (10 g 0.068 mol)in water (100 ml). The reaction mixture was heated under reflux for twodays, then was allowed to cool to room temperature and quenched withwater (150 ml). The solution was adjusted to pH 7 with 1M HCl andextracted with ether (3×100 ml). The organic layers combined were thenwashed with saturated NH₄Cl (150 ml) and brine (150 ml), dried (MgSO₄),and the solvent was removed under reduced pressure, to provide 6.63 g ofthe above-titled compound as a colorless liquid (85% yield). ¹H NMRCDCl₃, δ (ppm): 4.40-4.50 (m, 1H), 3.90-3.75 (m, 1H), 3.38 (t, J=6.8 Hz,1H), 2.97 (d, J=9.3 Hz, 1H), 2.50 (brs, 1H, OH), 1.90-1.20 (m, 12H),0.84 (s, 3H), 0.86 (s, 3H); ¹³C NMR CDCl₃, δ (ppm): 99.0, 76.2, 62.3,61.8, 38.8, 34.0, 33.4, 30.5, 25.4, 24.4, 24.3, 19.9, 19.3.

STEPS E and F (Compound A): A suspension of NaH (1.05 g of 60%dispension in mineral oil, washed with petroleum ether (3×25 ml) underN₂ and dried in a N₂ flow, 26.1 mmol) in 30 ml of freshly distilled THFwas cooled to 0° C., then2,2-dimethyl-5-hydroxy-l(tetrahydropyranyloxy)hexane (2 g, 8.69 mmol) in50 ml of THF was added dropwise. The mixture was stirred at roomtemperature for 30 min, then heated at 60° C. for 1 hr, and finallystirred overnight at room temperature. The suspension was cooled to 0°C., when 6-bromo-2,2-dimethyl-1-(tetrahydropyranyloxy)hexane (2.54 g,0.00869 mol) in 50 ml of THF was added dropwise. The resulting mixturewas heated at reflux for ca. 36 h, then diluted with 200 ml ofice-water, and most of the solvent was removed under vacuum. Theresulting residue was extracted with ether (3×150 ml), the combinedetheral extracts were washed with saturated NH₄Cl (200 ml), brine (200ml), and dried (Na₂SO₄). The solvent was then removed in vacuo to give 2g of crude product in the form of a yellow oil, containing ca. 60% ofbis(5,5-dimethyl-6(tetrahydropyranyloxy)hexyl)ether. The crude productwas dissolved in acetone (50 ml), stirred with 1 M HCl (50 ml) at 5° C.for 3 h and then left under stirring at room temperature for 3 days. Anaqueous saturated NaHCO₃ solution was added to adjust to pH 7 and thenthe mixture was extracted with ether (3×100 ml). The extract was washedwith sat. NH₄Cl (150 ml) and brine (150 ml), then dried (Na₂SO₄). Thesolvent was removed under vacuum to give ca. 1.5 g of yellow oil, whichwas subsequently fractionated, to provide Compound A as a yellow residue(1 g) (42% yield over two steps). ¹H-1 NMR CDCl₃, δ (ppm): 3.42 (t,J=6.8 Hz, 4H), 3.20 (s, 4H), 2.80 (brs, 2H), 1.48 (qv, J=6.8 Hz, 41H),1.10-1.30 (m, 8H), 0.76 (s, 12H); ¹³C NMR CDCl₃, δ (ppm): 71.1, 70.6,38.1, 34.8, 30.2, 23.8, 20.3. HRMS (POS FAB NBA) 275.257. Calcd forC₁₆H₃₅O₃ 275.258 (M+1).

7. EXAMPLE Synthesis of Compounds of formula XL, XLI, and XLII 7.1.Bis(5-phosphoryl-5-methylhexyl)ether Tetrasodium Salt

Bis(5-hydroxy-5-methylhexyl)ether: In a 250 ml 3-neck round-bottomedflask fitted with condenser, dropping funnel pressure equalizer andmagnetic stirrer, purged with argon and maintained under argon, wereadded 30 ml solution of methylmagnesium iodide, 3M in diethyl ether(0.09 mole Grignard reagent), and 30 ml diethyl ether.bis((Carboxymethyl)butyl)ether (3.6 g, 0.015 mole) (prepared as an oilfrom 4,4′-dicarboxybutyl ether, K. Alexander et al., 1948, J. Am. Chem.Soc. 70:1839 and diazomethane) in 20 ml diethyl ether was addeddropwise, with a slow rate, to allow a gentle reflux. After the additionwas complete, the reaction was allowed to reach the room temperature,and then was left under stirring for four hours. The reaction mixturewas cautiously poured onto 200 ml of a mixture of saturated aqueousammonium chloride and 200 ml ice, and was stirred until no more solidwas observed at the interface of the ethereal and aqueous layers. Theorganic layer was then separated in a separatory funnel, and the aqueouslayer was extracted four times, each time with 75 ml diethyl ether. Theethereal layers combined were dried over sodium sulfate, the solventevaporated in vacuum, and the organic residue was dried under vacuum for2 hr. An amount of 3.3 g (85% yield) ofbis(5-hydroxy-5-methylhexyl)ether was obtained, which was used withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ ppm, 3.40 (t, J=7.4 Hz,4H), 1.60 (brs, OH, 2H), 1.58 (qv, J=6.2 Hz, 4H), 1.50-1.40 (m, 8H),1.21 (s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ ppm, 70.9, 70.7, 43.6, 30.2,29.3, 21.1.

Bis-(5-Dibenzyloxyphosphoryl-5-methylhexyl)ether: A solution ofbis(5-hydroxy-5-methylhexyl)ether (1.5 g, 5 mmol) in 200 mL of CH₂Cl₂and 1H-tetrazole (2.38 g, 34 mmol) was stirred at room temperature,while a solution of dibenzyl N,N-diisopropylphosphoramidite (5.45 g, 16mmol) in 50 mL of CH₂Cl₂ was added. The mixture was stirred at roomtemperature for 1 h and cooled to −40° C., m-CPBA (70%, 4.5 g) in 50 mlCH₂Cl₂ was added. The reaction was stirred for 30 min at 0° C. and then30 min at room temperature. The mixture was washed (10% aqueous NaHCO₃),dried (Na₂SO₄), concentrated, and purified via chromatography (SiO₂using 50% EtOAc-pentane) to give 2.1 g (55%) ofbis-(5-Dibenzyloxyphosphoryl-5-methylhexyl)ether as a viscous colorlessoil: ¹H NMR (300 MHz, CDCl₃) δ ppm 7.40-7.20 (m, 20H, phenyl), 4.95-5.05(m, 8H), 3.36 (t, J=7 Hz, 4H), 1.80-1.20 (m, 8H), 1.45 (s, 12H); ¹³C NMR(75 MHz, CDCl₃) 5 ppm, 128.6-127.5 (m), 70.6, 68.7 (J=6.8 Hz), 67.3(J=6.0 Hz), 42.7 (J=4.0 Hz), 29.9, 27.5 (J=3.7 Hz), 20.9; HRMS (POS FAB)767.347. Calcd for C₄₂H₅₇O₉P₂ 767.347.

Bis-(5-Phosphoryl-5-methylhexyl)ether tetrasodium salt: A solution ofbis(dibenzylphosphate) (3.4 g, 4.4 mmol), NaHCO₃ (1.4 g, 17.6 mmol), andPd/C (10%, 1.8 g) in EtOH—H₂O (5:1 v/v, 300 mL) was shaken at 54 psiinitial pressure for 2 h. The catalyst was filtered off and washed with300 mL of water. The mixed solutions were filtered through a membranefilter, and then the solvent was removed under vacuum. The residue wasrecovered in 100 mL water, extracted with CHCl₃ and the aqueous layerfiltered through a membrane filter. Removal of water by lyophilizationgave 2 of solid Bis-(5-Phosphoryl-5-methylhexyl)ether tetrasodium salt,yield 70%: ¹H NMR (300 MHz, D₂O) δ ppm, 3.28 (t, J=5.0 Hz, 4H), 1.28(qv, J=5.0 Hz, 4H), 1.20-1.10 (m, 8H), 1.10 (s, 12H); ¹³C NMR (75 MHz,CDCl₃) δ ppm, 77.7 (J=7.1 Hz), 70.8, 42.9 (J=4.8 Hz), 27.2 (J=3.2 Hz),23.8, 20.8; ESI/MS (m/z) 494 (M), 406 (M+4H-4Na).

7.2. Bis(5-Phosphoryl-5-methylpenyl)ether Tetrasodium Salt

Bis-(4-Hydroxy-4-methylpentyl)ether: In a 250 ml 3-neck round-bottomedflask fitted with condenser, dropping funnel pressure equalizer andmagnetic stirrer, purged with argon and maintained under argon, wereadded 90 ml solution of methylmagnesium iodide, 3M in diethyl ether(0.27 mole Grignard reagent), and 90 ml diethyl ether.bis((Carboxymethyl)propyl)ether (9.81 g, 0.045 mole) (prepared as an oilfrom 4,4′-dicarboxybutyl ether, W. Reppe et al., Ann. Chem. 1955, 596,169 and diazomethane) in 20 ml diethyl ether was added dropwise, with aslow rate, to allow a gentle reflux. After the addition was complete,the reaction was allowed to reach the room temperature, and then wasleft under stirring for four hours. The reaction mixture was cautiouslypoured onto 500 ml of a mixture of aq. satd. ammonium chloride and 500ml ice, and was stirred until no more solid was observed at theinterface of the ethereal and aqueous layers. The organic layer was thenseparated in a separatory funnel, and the aqueous layer was extractedfour times, each time with 75 ml diethyl ether. The ethereal layerscombined were dried on and, sodium sulfate, the solvent evaporated invacuum, and the organic residue containing thebis-(4-hydroxy-4-methylpentyl)ether was dried under vacuum for 2 hr. Anamount of 9.6 g of diol (98% yield) was obtained as a pale-yellow oil,and was used without further purification. ¹H NMR (300 MHz, CDCl₃) δppm, 3.40 (t, J=6.2 Hz, 4H), 3.00 (brs, OH, 2H), 1.60-1.40 (m, 8H), 1.10(s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ ppm, 71.3, 70.0, 40.4, 29.0, 24.4.

Bis(4-Dibenzyloxyphosphoryl-4-methylpentyl)ether: A solution of diol(1.33 g, 6 mmol) in 200 mL of CH₂Cl₂ and 1H-tetrazole (2.38 g, 34 mmol)was stirred at room temperature, while a solution of dibenzylN,N-diisopropylphosphoramidite (5.45 g, 16 mmol) in 50 mL of CH₂Cl₂ wasadded. The mixture was stirred at room temperature for 1 h and cooled to−40° C., m-CPBA (70%, 4.5 g) in 50 ml CH₂Cl₂ was added, and the reactionwas stirred for 30 min at 0° C. and then 30 min at room temperature. Themixture was washed (10% aqueous NaHCO₃), dried (Na₂SO₄), concentrated,and purified via chromatography (SiO₂ using 50% EtOAc-pentane) to give 6g (55%) of bis(4-Dibenzyloxyphosphoryl-4-methylpentyl)ether as a viscouscolorless oil: ¹H NMR ppm (300 MHz, CDCl₃) d 7.4-7.2 (m, 20H, phenyl),5.2-4.8 (m, 8H), 3.4-3.6 (m, 2H), 1.8-1.6 (m, 8H), 1.5 (s, 6H), 1.1 (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ ppm, 135.9-135.2 (m), 127-129 (m), 85.3(J=7.5 Hz), (71.3, 70.6 (C1, C1′)), 68.9 (J=3.0 Hz), 67.3 (J=5.2 Hz),(45.1 (J=4.0 Hz), 39.3 (J=4.0 Hz) (C4, C4′)), 40.7, 29.2, 27.4 (J=3.0Hz), 24.6, 24.3 (C3, C3′), 18.1; HRMS (POS FAB) 739.317. Calcd forC₄₀H₅₃O₉P₂ 739.316.

Bis(4-Phosphoryl-4-methylpenyl)ether tetrasodium salt: A solution ofbis(dibenzylphosphate) (3.1 g, 4.2 mmol), NaHCO₃ (1.4 g, 17.6 mmol), andPd/C (10%, 1.8 g) in EtOH—H₂O (5:1 v/v, 300 mL) was shaken at 54 psiinitial pressure for 2 h. The catalyst was filtered off and washed with300 mL of water. The mixed solutions were filtered through a membranefilter, then the solvent was removed under vacuum. The residue wasrecovered in 100 mL water, extracted with CHCl₃ and the aqueous layerfiltered through a membrane filter. Removal of water by lyophilizationgave 3.7 of solid bis(4-Phosphoryl-4-methylpenyl)ether tetrasodium salt,yield 92%: ¹H NMR (300 MHz, D₂O) δ ppm 3.30-3.20 (m, 4H); 1.80-1.60 (m,8H), 1.70 (s, 12H); ¹³C NMR (75 MHz, D₂O) δ ppm 81.0 (m), 29.6,29.0,27.1, 23.9; ESI/MS (m/z) 467 (M+H), 378 (M+4H−4Na).

7.3.2,12-Dimethyltridecyl 2,12-diphosphate Tetrasodium Salt

2,12-Dimethyltridecane-2,12-diol: In a 500 ml 3-neck round-bottomedflask fitted with condenser, dropping funnel pressure equalizer andmagnetic stirrer, purged with argon and maintained under argon, wereadded 80 ml solution of methylmagnesium iodide, 3M in diethyl ether(0.09 mole Grignard reagent), and 100 ml diethyl ether. Dimethylundecanedioate (14 g, 0.057 mole, Fluka) in 50 ml diethyl ether wasadded dropwise, with a slow rate, to allow a gentle reflux. After theaddition was complete, the reaction was allowed to reach the roomtemperature, then was left under stirring for four hours. The reactionmixture was cautiously poured onto 500 ml of a mixture of aq. satd.ammonium chloride and 500 ml ice, and was stirred until no more solidwas observed at the interface of the ethereal and aqueous layers. Theorganic layer was then separated in a separatory funnel, and the aqueouslayer was extracted four times, each time with 100 ml diethyl ether. Theethereal layers combined were dried on anh. sodium sulfate, the solventevaporated in vacuum, and the organic residue was dried under vacuum for2 hr. An amount of 12 g of 2,12-Dimethyltridecane-2,12-diol (95% yield)was obtained, as white crystals m.p 58.5-59.5° C. and used withoutpurification. ¹H NMR (300 MHz, CDCl₃) δ ppm, 1.60 (brs, OH, 2H),1.50-1.25 (m, 18H), 1.20 (s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ ppm,70.9,43.9,30.1, 29.5, 29.4, 29.1, 24.2.

2,12-Dibenzyloxyphosphoryl-2,12-dimethyltridecane: A solution of diol(3.4 g, 13.7 mmol) in 650 mL of CH₂Cl₂ and 1H-tetrazole (6.51 mg, 93mmol) was stirred at room temperature, while a solution of dibenzylN,N-diisopropylphosphoramidite (15.17 g, 44 mmol) in 50 mL of CH₂Cl₂ wasadded. The mixture was stirred at room temperature for 1 h and cooled to−40° C., m-CPBA (70%, 12.8 g, 0.055 mol) in 120 ml CH₂Cl₂ was added, andthe reaction was stirred for 30 min at 0° C. and then 30 min at roomtemperature. The mixture was washed (10% aqueous NaHCO₃), dried(Na₂SO₄), concentrated and chromatographed on SiO₂ using 50%EtOAc-pentane, to give 5.5 g (53%) of2,12-Dibenzyloxyphosphoryl-2,12-dimethyltridecane colorless oil: ¹H NMR(300 MHz, CDCl₃) δ ppm, 7.40-7.20 (m, 2011, phenyl), 5.05-4.95 (m, 4H),1.70-1.20 (m, 10H), 1.22 (s, 12H), 1.20-1.10 (m. 8H); ¹³C NMR (75 MHz,CDCl₃) δ ppm, 136.1 (m), 128.4-127.5 (m), 85.9 (J=7.0 Hz), 68.6 (J=7.0Hz), 67.1 (J=6.0 Hz), 42.7 (J=4.0 Hz), 29.8, 29.5, 27.5 (J=3.7 Hz),24.1; LRMS (m/z) (M⁺) 766.

2,12-Dimethyltridecyl 2,12-diphosphate tetrasodium salt: A solution ofbis(dibenzylphosphate) (3.4 g, 4.4 mmol), NaHCO₃ (1.4 g, 17.6 mmol), andPd/C (10%, 1.8 g) in EtOH—H₂O (5:1 v/v, 300 mL) was shaken at 54 psiinitial pressure for 2 h. The catalyst was filtered off and washed with300 mL of water. The mixed solutions were filtered through a membranefilter, then the solvent was removed under vacuum. The residue wasrecovered in 100 mL water, extracted with CHCl₃ and the aqueous layerfiltered through a membrane filter. Removal of water by lyophilizationgave 1.4 of 2,12-dimethyltridecyl 2,12-diphosphate tetrasodium salt,yield 98%: ¹H NMR (300 MHz, D₂O) δ ppm, 1.30-1.20 (m, 2H); 1.10-1.00 (m,8H), 1.10 (s, 12H); ³¹P NMR (258 MHz, D₂O) δ ppm, 4.20; ESI/MS (m/z) 403(M−H−4Na), 471 (M−Na).

8. EXAMPLE Effects of Illustrative Compounds of the Invention onLDL-Cholesterol, HDL-Cholesterol and Triglyceride Levels in MaleSprague-Dawley Rats

Illustrative compounds of the invention were administered daily at adose of 100 mg/kg to chow fed male Sprague-Dawley rats for seven days inthe morning by oral gavage in 1.5% carboxymethylcellulose/0.2% Tween-20(dosing vehicle). Animals were weighed daily. Animals were allowed freeaccess to rodent chow and water throughout the study. After the seventhdose, animals were sacrificed in the evening and blood serum was assayedfor lipoprotein cholesterol profiles, serum triglycerides, totalcholesterol VLDL, LDL, and HDL cholesterol, and the ratio of HDLcholesterol to that of VLDL plus LDL cholesterol, apolipoproteins A-I,C-II, C-III, and E by immunoelectrophoresis, and percent weight gain.

Table 1 shows the effect of Compound A, Compound B, Compound C, CompoundD and Compound E on serum LDL-cholesterol, HDL-cholesterol andtriglycerides in chow-fed male Sprague-Dawley rats following-seven daysof treatment. The five compounds were tested in two separateexperiments. In each experiment, the experimental data were normalizedagainst a control group of rats which received the dosing vehicle alone.daily for seven days in the morning by oral gavage in 1.5%carboxymethylcellulose/0.2% Tween-20. Troglitazone was obtainedcommercially. Finely crushed tablets were suspended in vehicle fordosing. Orbital blood samples were obtained following a six-hour fastprior to the initial dose and also following the seventh dose.

Blood serum was assayed for total cholesterol and triglycerides (FIG.5), lipoprotein cholesterol profiles (FIG. 6), VLDL plus LDL cholesterolcombined (also referred to as apo B containing lipoprotein cholesterolor non-HDL cholesterol), HDL cholesterol, and the ratio of HDLcholesterol to that of VLDL plus LDL cholesterol (FIG. 7), serumglucose, and non-esterified fatty acids (FIG. 8), and percent weightgain (FIG. 9). In the Zucker rats, Compound A increased total serumcholesterol by 3.3-fold after one week of treatment, while the vehicleand troglitazone treatment resulted in a reduction of this variable(FIG. 5A). Serum triglycerides were markedly reduced with Compound Atreatment 68% (FIG. 5B). Lipoprotein cholesterol profiles show treatmentwith Compound A resulted in a marked alteration in the distribution ofcholesterol among lipoproteins (FIG. 6). In particular, Compound Acaused a marked elevation in HDL cholesterol after one week oftreatment. Using the serum total cholesterol values (FIG. 5A) and thelipoprotein cholesterol distribution (FIG. 6), the amount of cholesterolassociated with non-HDL (i.e., VLDL plus LDL) and HDL were determined(FIG. 7). Compound A increased non-HDL cholesterol slightly (+10.3%) butsignificantly increased HDL cholesterol 3.9-fold. In contrast,troglitazone reduced non-HDL and HDL cholesterol by 67% and 4%,respectively. When these data are expressed as a ratio of HDL/non-HDLcholesterol it can be clearly seen that Compound A markedly improves theratio from 4.2 (pre-treatment) to 14.9 (one week treatment), a 3.6-foldincrease.

Typically, impaired glucose tolerance is the metabolic symptom of eightto 12 week-old-obese female Zucker rats. The animals are able tomaintain normal to slightly elevated glucose levels at the expense ofelevated insulin levels. As shown in FIG. 8A, pre-treatment andpost-treatment serum glucose levels were similar for all treatmentswithin normal range. Compound A treatment did not induce a hypoglycemicstate. Typically, these animals also have elevated non-esterified fattyacids in this pre-diabetic state. These levels were reduced withCompound A and troglitazone treatment by 52% and 65%, respectively (FIG.8B).

One adverse effect of troglitazone treatment is weight gain, largely dueto increased adipose mass. As shown in FIG. 9, troglitazone treatment infemale Zucker rats caused the greatest increase in weight gain (+11.6%).Zucker rats treated with vehicle

Treatment LDL- HDL- Duration Dose Cholesterol Cholesterol TriglycerideCompound (N) (days) (mg/kg/day) (% change) (% change) (% change) Control5 7 0 (0) (0) (0) Compound A 5 7 100 −27.7 +21.1 +7.6  Compound B 5 7100 +23.2 +40.7 −31.1 Compound C 5 7 100  −4.0 +11.6 +32.6 Compound D 57 100 −17.0 +13.3 +28.0 Compound E 5 7 100 −41.0 +49.1 −30.5

The data tabulated above and other data collected from these experimentsare graphically depicted for Compound A. FIG. 1 showslipoprotein-cholesterol profiles, which indicate that treatment withCompound A results in reduction of LDL cholesterol and elevation of HDLcholesterol when compared to animals treated with the dosing vehiclealone. Compound A treatment also reduces serum triglycerides by 31% andelevates total serum cholesterol by 26% (FIG. 2). The change in totalcholesterol was reflected by no change in VLDL cholesterol, a reductionin LDL cholesterol by 41% and an elevation in HDL cholesterol by 49%.The ratio of HDL to non-HDL cholesterol (VLDL plus LDL) improved from2.6+0.2 to 6.2±1.0 following treatment with Compound A, a 2.44 foldimprovement in the ratio (FIG. 2). Compared to control treatment,Compound A-treatment of the rats elevated apolipoprotein A-I and E by16% and 46%, respectively, and reduced apolipoprotein C-II and C-III by20% and 16%, respectively (FIG. 3). Compound A also reduced thepercentage body weight gain resulting from growth compared to thecontrol group after seven days of treatment (63.4±1.9% vs. 68.3±1.2%weight gain; FIG. 4). Accordingly, Compounds A, B, C, D, and E orpharmaceutically acceptable salts thereof are useful for promotinghigher levels of circulating HDL, the “good” cholesterol, and raisingthe ratio of HDL:non-HDL cholesterol in the blood.

9. EXAMPLE Effects of Illustrative Compounds of the Invention onLDL-Cholesterol, HDL-Cholesterol and Triglyceride Levels in Obese FemaleZucker Rats 9.1. Experiment A

Dosing vehicle, Compound A (86 mg/kg of body weight) or troglitazone(120 mg/kg of body weight) was administered to eight week old femaleobese Zucker rats alone showed a 6.6% increased weight after seven days,while Zucker rats treated with Compound A showed a 5.4% increase in bodyweight.

Accordingly, Compound A, or a pharmaceutically acceptable salt thereof,is useful for reducing serum triglycerides, elevating circulating HDL,improving the ratio of HDL:LDL in the blood, without the adverse sideeffect of promoting weight gain in a patient to whom the compound isadministered.

9.2. Experiments B, C, D, & E

In a number of different experiments, illustrative compounds of theinvention and troglitazone were administered daily at various doses to10-week old chow fed obese female Zucker rats for 14 days in the morningby oral gavage in 1.5% carboxymethylcellulose/0.2% Tween-20 (dosingvehicle). Animals were weighed daily. Animals were allowed free accessto rodent chow and water throughout the study. Blood glucose wasdetermined after a 6-hour fast in the afternoon without anesthesia froma tail vein. Serum was also prepared from a blood sample subsequentlyobtained from the orbital venous plexus (with O₂/CO₂ anesthesia) priorto and after one week treatment and used lipid and insulindeterminations. At two weeks, blood glucose was again determined after a6-hour fast without anesthesia from a tail vein. Soon thereafter,animals were sacrificed by CO₂ inhalation in the evening and cardiacblood serum was collected and assessed for various lipids and insulin.Body weight was determined daily prior to dosing and at the time ofeuthanasia. Table 2 shows effects of the Compound A and Compound Bcompared to troglitazone on the percent change in serum non-HDLcholesterol, HDL-cholesterol, triglyceride and body weight (relative topretreatment values) in fasted (6 hours) chow-fed obese female Zuckerrats.

TABLE 2 Non Treatment Dose HDL-Cholesterol HDL-Cholestrol TriglyceridesBody Weight Gain Experment Compound (N) Duration (days) (mg/kg/day) (%of Pretreatment) (% of Pretreatment) (% of Pretreatment) (% ofPretreatment) B Control 3 14 0 +217.5 −43.1 −31.9 +10.7 B Compound B 314 100 +257.1 −23.3 +24.6 +12.0 B Troglitazone 2 14 120 −44.0 +44.2−76.6 +21.7 C Control 4 14 0 −25.6 −29.8 −11.2 +16.7 C Compound A 3 14 1−25.6 −24.1 −8.8 +16.7 C Compound A 2 14 3 −29.6 −3.7 −24.6 +17.5 CCompound A 3 14 10 −14.2 +154.4 −50.9 +10.7 C Compound A 3 14 30 +38.4+369.7 −42.0 +11.3 C Compound A 3 14 100 +45.1 +801.8 −57.0 +9.2 CTroglitazone 3 14 12 −10.6 +1.9 +10.7 +20.2 C Troglitazone 3 14 40 −50.5+36.1 −59.6 +21.2 C Troglitazone 3 14 120 −67.5 +122.4 −79.2 +25.5 DControl 3 14 0 +15.2 −12.2 +1.6 +10.6 D Compound A 3 14 10 +49.3 +133.9−11.1 +2.2 D Compound A 2 14 100 +7.5 +187.9 −62.9 +4.5 D Troglitazone 314 120 −51.0 +41.3 −65.9 +13.8 E Control 3 14 0 −13.1 +10.2 +12.0 +21.9E Compound A 1 14 100 +7.2 +232.1 −43.2 +19.1 E Troglitazone 3 14 120−67.4 +47.9 −69.4 +14.4

Generally, Compound A improved the ratio of non-HDL cholesterol to HDLcholesterol content relative to both control animals andtroglitazone-treated animals. Additionally, Compound A generally reducedserum triglyceride content and did not cause the body weight increasesseen in troglitazone-treated animals.

The data from Experiment C concerning Compound A are graphicallydepicted in FIGS. 10-16. Compound A treatment reduced serum triglyceridelevels at all doses. Reduction in serum triglycerides was dose dependentwith a minimal effective dose of approximately 3 mg/kg (FIG. 10).Reduction of triglycerides by troglitazone was observed only at doses of40 and 120 mg/kg (FIG. 10).

Compound A treatment elevated serum total cholesterol in a dose- andtreatment duration-dependent manner beginning at a dose of approximately10 mg/kg/day (FIG. 11). With longer treatment (i.e. two weeks verses oneweek) the elevation of serum total cholesterol was greater for allCompound A doses greater or equal to 10 mg/kg (FIG. 11). Fortroglitazone, total cholesterol was only modestly elevated at thehighest dose (120 mg/kg) and only after two weeks of treatment (FIG.11). Elevation in serum cholesterol observed with Compound A werelargely reflected by a marked elevation in HDL-cholesterol. The rise inHDL-cholesterol caused by Compound A was dose- and treatmentduration-dependent. At the highest Compound A dose used (i.e. 100mg/kg), HDL-cholesterol was elevated 9-fold (802% increase) after twoweeks of treatment (FIG. 11). Troglitazone caused a markedly lowerelevation in HDL at the 120 mg/kg dose (122% increase).

Blood glucose (FIG. 12) and serum insulin levels (FIG. 13) weredetermined from fasted rats just prior to and following one and twoweeks of treatment. Blood glucose was maintained at slightly elevatedlevels for 10-12 week old obese Zucker rats during treatment with alldoses of Compound A and troglitazone, with the exception of the 100mg/kg and 40 mg/kg doses, respectively, whereby both compounds showed atendency to lower blood glucose. For troglitazone, this glucose loweringeffect was not dose dependent, since it did not occur at 120 mg/kg.Relative to pretreatment values, serum insulin (FIG. 13) in controlanimals sharply rose as the animals became older. At dosages of 1 and 3mg/kg of Compound A, a similar sharp rise in insulin levels wasobserved. However, at the higher Compound A doses, this sharp rise inserum insulin was largely curtailed or minimized. For troglitazone,serum insulin levels were reduced following two weeks of treatment atall doses tested (FIG. 13). One measure of improved insulin sensitivity(i.e. as impaired glucose tolerance progresses as the animals age), is asustained or improved ratio of fasting serum glucose to insulin. Theglucose to insulin ratio in these animals is shown in FIG. 14. In thecontrol and the 1 and 3 mg/kg of Compound A groups, the glucose toinsulin ratio declined by approximately ⅓ to ½ as the animals aged twoweeks. In contrast, at 10 and 30 mg/kg Compound A, the glucose toinsulin ratio was sustained at pretreatment levels. At 100 mg/kg ofCompound A, the glucose to insulin ratio was reduced, suggesting thisdose superseded the optimal dose for sustaining insulin sensitivity forthe compound. Troglitazone at all doses sustained the glucose to insulinratio after one week treatment and increased this ratio after two weeksof treatment (FIG. 14).

FIG. 15 shows the weekly percent weight gain in the Zucker rats duringtreatment. Control rats gained 9.1 and 16 percent of their initialweight after one and two weeks respectively. With Compound A treatment,all treatment groups gained weight. At the lower doses (1 and 3 mg/kg)weight gain was similar to controls. However, weight gain was markedlyreduced at 10, 30 and 100 mg/kg of Compound A after both one and twoweeks of treatment, suggesting Compound A may have thermogenicproperties. In contrast, troglitazone treatment caused increased weightgain after one week at 120 mg/kg and increased weight gain after twoweeks at all treatment doses (12, 40 and 120 mg/kg).

Percent liver to body weight was determined after two weeks of treatmentat the time of sacrifice (FIG. 16). Following Compound A treatment,liver to body weight increased in a dose dependent manner. Fortroglitazone, liver to body weight was reduced at all doses. The gain inliver to body weight in rats suggests to the inventors, withoutintending any limitation as to the mechanism by which the compounds ofthe invention act, that Compound A may be a peroxisomal proliferatoractivator receptor ligand.

Accordingly, Compound A, or a pharmaceutically acceptable salt thereof,is useful for improving the ratio HDL:non-HDL cholesterol in the blood,reducing serum triglycerides, elevating HDL-cholesterol, lowering bloodglucose, and/or improving insulin sensitivity, without the adverse sideeffect of promoting weight gain in a patient to whom the compound isadministered

10. EXAMPLE Effect of Compound A on Lipoprotein Cholesterol Profile inLDL Receptor-Deficient Mice

Homozygous familial hypercholesterolemia is a rare human disease(˜1/1,000,000) characterized by absent or defective LDL receptors,markedly elevated serum LDL cholesterol levels and very early and severeonset of atherosclerosis. The more common form of this disease inhumans, heterozygous familial hypercholesterolemia, occurs in about onein every 500 humans. Patients with the heterozygous form of this diseasealso present with elevated LDL levels and early onset ofatherosclerosis.

The effect of Compound A on LDL levels in a murine model of homozygousfamilial hypercholesterolemia (Ishibashi et al., 1993, J. Clin. Invest.92:883-893; Ishibashi et al., 1994, J. Clin. Invest. 93:1885-1893) wasstudied. LDL receptor-deficient mice have elevated LDL cholesterolrelative to wild type mice when fed a chow diet. When fedcholesterol-enriched diets, these mice develop atherosclerosis.

FIG. 17 shows the lipoprotein cholesterol profiles (Bisgaier et al., J.Lipid Res. 38:2502-2515) of 4 chow-fed female LDL receptor deficientmice prior to and following therapy with 300 mg/kg/day of Compound A.All mice showed a rapid and significant reduction in LDL cholesterolafter one week of treatment. In addition, FIG. 17 shows that Compound Acaused HDL elevation in all treated mice.

Accordingly, Compound A, or a pharmaceutically acceptable salt thereof,is useful for reducing circulating LDL levels and/or increasingcirculating HDL in a patient with a dyslipidemia, including homozygousfamilial hypercholesterolemia.

11. EXAMPLE Effect of Illustrative Compounds of the Invention on theSynthesis of Non-Saponified and Saponified Lipids in HepatocytesIsolated From a Male Sprague-Dawley Rat

A male Sprague-Dawley rat was anesthetized by administration of sodiumpentobarbitol by intraparitoneal injection at 50 mg/kg. In situperfusion of the liver was performed as follows. The abdomen of theanimal was opened, the portal vein canulated, and the liver perfusedwith WOSH solution (149 mM NaCl, 9.2 mM Na HEPES, 1.7 mM Fructose, 0.5mM EGTA, 0.029 mM Phenol red, 10 U/ml heparin, pH 7.5) at a flow rate of30 ml/min for 6 minutes. To digest the liver, DSC solution (6.7 mM KCl,143 mM NaCl, 9.2 mM Na HEPES, 5 mM CaCl₂-2H₂O, 1.7 mM Fructose, 0.029 mMPhenol red, 0.2% BSA, 100 U/ml collagenase Type I, 93 U/mlHyaluronidase, 160 BAEE/ml trypsin inhibitor, pH 7.5) was perfusedthrough the liver at a flow rate of 30 ml/min for 6 minutes at atemperature of 37° C. After digestion, cells were dispersed in asolution of DMEM− (DMEM containing 2 mM GlutMax-1,0.2% BSA, 5% FBS, 12nM insulin, 1.2 μM hydrocortisone) to stop the digestion process. Thecrude cell suspension was filtered through three layers of stainlesssteel mesh with pore sizes of 250, 106, and 75 μm respectively. Filteredcells were centrifuged at 50× g for two minutes and the supernatantdiscarded. The resulting cell pellet was resuspended in DMEM andcentrifuged again. This final cell pellet was resuspended in DMEM+HSsolution (DMEM containing 2 mM GlutMax-1,20 nM delta-aminolevulinicacid, 17.4 mM MEM non-essential amino acids, 20% FBS, 12 nM insulin, 1.2μM hydrocortisone) and plated to form monolayer cultures at a density of100×10³ cells/cm² on collagen coated culture dishes. Four hours afterinitial plating, media was changed to DMEM+ (DMEM containing 2 mMGlutMax-1, 20 nM delta-aminolevulinic acid, 17.4 mM MEM non-essentialamino acids, 10% FBS, 12 nM insulin, 1.2 μM hydrocortisone) and remainedon cells overnight.

To test the effect of illustrative compounds of the invention onsynthesis rates of non-saponified and saponified lipids, the monolayercultures were exposed to 1 μM of lovastatin or 100 μM Compound A, B, D,E or F in DMEM+ containing 1 μCi/ml ¹⁴C-acetate. Control cells wereexposed to the same media lacking lovastatin or the test compounds. Allcells were exposed to 0.1% DMSO. Metabolic labeling with ¹⁴C-acetatecontinued for 2 hr at 37° C. After labeling, cells were washed twicewith 1 ml of PBS followed by lysing in 1 ml of deionized water. Cellswere scraped from the dishes, transferred to glass tubes and sonicated.2.5 ml of 2:1 chloroform/methanol mixture was added followed by 1.5 mlof Phosphate Buffered Saline (PBS). To correct for extraction efficiencyin the upcoming extractions, 3000 dpm of ³H-cholesterol was added toeach tube. Tubes were shaken for 30 min. to extract lipids into theorganic phase followed by centrifugation for 10 minutes at 1000× g toseparate the organic and aqueous phases. The lower organic phasecontaining total lipids was removed and placed in a new tube. Theorganic solution was evaporated under N₂. The dry lipid extract wasresuspended in 1 ml of 93% ethanol containing 1 M KOH and placed at 70°C. for 2.5 hours. After the reaction and cooling, 2 ml of hexane and 2.5ml of water was added to each tube followed by rigorous shaking for 10min. Tubes were centrifuged for 10 min. at 1000× g and the organic (top)layer containing the non-saponified lipids was transferred to a new tubefollowed by evaporation of the organic solvent under N₂. The aqueousphase containing the saponified lipids was also transferred to a newtube. The non-saponified lipid extract, after drying, was resuspended intoluene and an aliquot of the suspension was added to a scintillationcocktail for radioactive counting. The number of ¹⁴C counts representingthe incorporation of ¹⁴C-acetate into non-saponified lipids wascorrected for extraction efficiency, based on the recovery of ³H countsextracted. To isolate saponified lipids, 1.5 ml of aqueous phasesolution was mixed with 400 μl of 1 M HCl, and then lipids wereextracted by the addition of 2.5 ml of 2:1 chloroform:methanol, 1.5 mlof PBS, and 1 ml of water followed by rigorous shaking and isolation ofthe organic phase. The organic phase from this extraction was evaporatedunder N₂ and resuspended in toluene. Its radioactivity was counted usingscintillant to provide the rate of ¹⁴C-acetate incorporation intosaponified lipid.

FIG. 18 shows the rates of saponified and non-saponified lipid synthesisfollowing treatment with lovastatin and illustrative compounds of theinvention. Data are represented as a percent of no compound treatment(control). Data are represented as the mean of three measurements +/−one standard deviation. The data indicate that illustrative compounds ofthe invention are useful for inhibiting saponified and/or non-saponifiedlipid synthesis. In particular, Compound A reduced the rate of bothsaponified and non-saponified lipid synthesis by at least 85% in the rathepatocytes. Compounds E and F also reduced the rates of saponifiedfatty acid synthesis. Accordingly, Compound A, or a pharmaceuticallyacceptable salt thereof, is useful for inhibiting the synthesis ofsaponified and/or non-saponified fatty acids. Compounds E and E, orpharmaceutically acceptable salts thereof, are also useful forinhibiting the synthesis of saponified fatty acids.

12. EXAMPLE Measurement of the Cytotoxicity of Illustrative Compounds ofthe Invention

To evaluate the effects of illustrative compounds of the invention oncytotoxicity, monolayer hepatocyte cultures were exposed to increasingconcentrations of up to 250 μM Compound A, B, C, or D in DMEM+ for 24hours. Control cells were exposed to the same media lacking a testcompound. All cells were exposed to 0.1% DMSO. The measure ofcytotoxicity, release of lactate dehydrogenase (LDH) from the cytosoliccompartment of hepatocyte monolayer cultures, reflects damage to theplasma membrane. The assay, based on the method of Wroblewski andLaDue,1955, Proc. Soc. Exp. Biol. Med. 90:210-213; see also Ulrich etal., 1995, Toxicol. Lett. 82/83:107-115, describing the use ofhepatocytes as models for hepatic toxicity), measures the LDH activityin tissue culture medium and a cell homogenate. Briefly, all the mediawere removed from plates and transferred to a separate plate. Followingremoval of media, attached cells were lysed with a hypotonicTris/Glycerol/EDTA buffer (0.1 M Tris, 20% glycerol, 1 mM EDTA pH 7.3).Activity of LDH in medium and cells was measured spectrophotometricallyby monitoring the rate of pyruvate reduction to lactate, coupled withoxidation of NADH; the rate of absorbance change was measured at 340 nm.Cytotoxicity was expressed as ratio using the following equation: (LDHin medium/(LDH in medium+LDH in solubilized hepatocytes))=R.

FIG. 19 shows the results of these experiments. At all concentrationstested, none of Compounds A, B, C, or D resulted in the secretion ofmore than approximately 25-30% of total LDH in the medium. For CompoundA, toxicity was assayed at 2.5-fold the compound's therapeuticallyeffective concentration. These experiments indicate that the toxicity ofthe compounds of the invention is low. Accordingly, Compounds A, B, Cand D, and pharmaceutically acceptable thereof, are potentially suitablefor human use without toxic side effects.

13. EXAMPLE Insulin Sensitization Effects of Compound A

The effects of Compound A on rate of differentiation of 3T3-L1 cellsfrom a “committed pre-adipocyte” to an “adipocyte” phenotype in theabsence or presence of insulin is tested. The differentiation of 3T3-L1cells to an adipocyte-like phenotype is highly dependent upon insulin.This insulin-dependent changes in cellular morphology and metabolism,including: expression of adipocyte-specific genes, greatly increasedlevels of glucose uptake and metabolism, induction of GLUT4 (andincreased expression of GLUT1) glucose transporters, greatly increasedlipid synthesis and deposition of intracellular lipid droplets. In thisassay the degree of differentiation was a reflection of the rate oflipid synthesis, as measured through incorporation of ¹⁴C-acetate over 2hours. Thus the ability of a compound to stimulate a submaximal insulinresponse would suggest an insulin-sensitizing activity (Kletzein et al.,1991, Molecular Pharm.41:393-398).

3T3-L1 stem cells were induced to differentiate with dexamethasone,isobutylmethylxanthine and insulin (Green and Kehinde, 1975, Cell5:19-27). Cells were plated in Dulbecco's modified Eagle mediumcontaining 10% calf serum and grown to confluence. Cells were thenrefreshed with 10% fetal calf serum, and treated with 0.5 mMisobutylmethylxanthine and 250 nM dexamethasone, but no additionalinsulin, for 48 hours. This treatment induced the differentiation of3T3-L1 cells into pre-adipocytes. Conversion of preadipocytes toadipocyte phenotype requires the removal of dexamethasone and thepresence of insulin, which stimulates differentiation of preadipocytesinto adipocytes in a concentration- and time-dependent manner. A maximalinsulin effect occurs at about 100 nM insulin, and leads to nearlycomplete (95-100%) conversion to adipocytes within 4 days.

The preadipocytes were then treated for 4 days with variousconcentrations of Compound A in 5% fetal calf serum in Dulbecco'smodified Eagles medium, with or without a submaximal concentration ofinsulin (30 nM). Following this four-day treatment, the predipocyteswere pulsed with 0.1 μCi ¹⁴C-acetate per well for 2 hours. Cell werethen washed with phosphate buffered saline, lysed with 0.1 N NaOH, and¹⁴C-acetate incorporation into lipids was determined using phaseseparation and liquid scintillation counting.

FIG. 20 shows the results of these experiments. Data are represented asthe mean +/− one standard deviation for three measurements. WithoutCompound A, ¹⁴C-acetate incorporation into lipids was 4201 DPM in thepresence of insulin and 545 DPM in the absence of insulin. In thepresence of Compound A, ¹⁴C-acetate incorporation increased byapproximately 40%, indicating that Compound A potentiates theinsulin-dependent increase in acetate incorporation. Accordingly,Compound A or a pharmaceutically acceptable salt thereof is suitable foruse as an insulin sensitizer.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art and are intended to fall within the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹, R², R³, andR⁴ are independently selected from the group consisting of(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; or R¹, R², and thecarbon to which they are attached are taken together to form a(C₃-C₇)cycloalkyl group; or R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₇)cycloalkyl group; or R¹,R², and the carbon to which they are attached are taken together to forma (C₃-C₇)cycloalkyl group and R³, R⁴, and the carbon to which they areattached are taken together to form a (C₃-C₇)cycloalkyl group, with theproviso that none of R¹, R², R³, or R⁴ is —(CH₂)₀₋₄C≡CH; n and m areindependent integers ranging from 0 to 4; one of K¹ and K² is

and the other of K¹ and K² is —C(O)OH or —C(O)OR₅; R⁵ is selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, and benzyl; eachR⁶ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl; R⁷ is selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl.